Bases moleculares de las neoplasias hematológicas

Desarrollo de estrategias terapéuticas basadas en células CART
Estudio del transcriptoma, epigenoma y metabolismo de las células plasmáticas tumorales del Mieloma múltiple
Mecanismos de regulación génica en leucemia aguda y síndromes mielodisplásicos
Papel de las alteraciones epigenéticas en la patogénesis y tratamiento de tumores hematológicos
Papel del nicho hematopoyético en los tumores hematológicos

Palabras Clave

Epigenómica
Histonas
Leucemia
Metabolismo
Metilación
Mieloma Múltiple
Nicho hematopoyético
Síndrome mielodisplásico

Publicaciones Científicas desde 2018

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Autores: Simoes Pinto, Cátia Patricia; Chillón, M. C.; Martínez-Cuadrón, D.; et al.

Título: Integrated flow cytometry and sequencing to reconstruct evolutionary patterns from dysplasia to acute myeloid leukemia

Revista: BLOOD ADVANCES

ISSN: 2473-9529 Vol.7 N° 1 2023 págs. 167 - 173

Resumen

Clonal evolution in acute myeloid leukemia (AML) originates long before diagnosis and is a dynamic process that may affect survival. However, it remains uninvestigated during routine diagnostic workups. We hypothesized that the mutational status of bone marrow dysplastic cells and leukemic blasts, analyzed at the onset of AML using integrated multidimensional flow cytometry (MFC) immunophenotyping and fluorescence-activated cell sorting (FACS) with next-generation sequencing (NGS), could reconstruct leukemogenesis. Dysplastic cells were detected by MFC in 285 of 348 (82%) newly diagnosed patients with AML. Presence of dysplasia according to MFC and World Health Organization criteria had no prognostic value in older adults. NGS of dysplastic cells and blasts isolated at diagnosis identified 3 evolutionary patterns: stable (n= 12 of 21), branching (n= 4 of 21), and clonal evolution (n= 5 of 21). In patients achieving complete response (CR), integrated MFC and FACS with NGS showed persistent measurable residual disease (MRD) in phenotypically normal cell types, as well as the acquisition of genetic traits associated with treatment resistance. Furthermore, whole-exome sequencing of dysplastic and leukemic cells at diagnosis and of MRD uncovered different clonal involvement in dysplastic myelo-erythropoiesis, leukemic transformation, and chemoresistance. Altogether, we showed that it is possible to reconstruct leukemogenesis in 80% of patients with newly diagnosed AML, using techniques other than single-cell multiomics.
Autores: Amundarain, A.; Pastor, F.; Prosper Cardoso, Felipe (Autor de correspondencia); et al.

Título: Aptamers, a new therapeutic opportunity for the treatment of multiple myeloma

Revista: CANCERS

ISSN: 2072-6694 Vol.14 N° 21 2022 págs. 5471

Resumen

Simple Summary Multiple Myeloma (MM) remains incurable due to high relapse rates and fast development of drug resistances. Monoclonal antibodies (mAb) have revolutionized MM treatment, opening the door to chemotherapy-free yet curative treatments. Nevertheless, antibody-based therapies face several difficulties which could be overcome by nucleic acid aptamers. Aptamers are short oligonucleotide ligands that bind their targets with great affinity and specificity, and can be easily conjugated to different cargoes for their cell-specific delivery. This review summarizes the aptamers that have been tested in MM so far with promising results, and proposes various strategies for the further development of aptamer-based strategies against MM. Multiple Myeloma (MM) remains an incurable disease due to high relapse rates and fast development of drug resistances. The introduction of monoclonal antibodies (mAb) has caused a paradigm shift in MM treatment, paving the way for targeted approaches with increased efficacy and reduced toxicities. Nevertheless, antibody-based therapies face several difficulties such as high immunogenicity, high production costs and limited conjugation capacity, which we believe could be overcome by the introduction of nucleic acid aptamers. Similar to antibodies, aptamers can bind to their targets with great affinity and specificity. However, their chemical nature reduces their immunogenicity and production costs, while it enables their conjugation to a wide variety of cargoes for their use as delivery agents. In this review, we summarize several aptamers that have been tested against MM specific targets with promising results, establishing the rationale for the further development of aptamer-based strategies against MM. In this direction, we believe that the study of novel plasma cell surface markers, the development of intracellular aptamers and further research on aptamers as building blocks for complex nanomedicines will lead to the generation of next-generation targeted approaches that will undoubtedly contribute to improve the management and life quality of MM patients.
Autores: Huerga Domínguez, Sofia; Villar Fernández, Sara; Prosper Cardoso, Felipe; et al.

Título: Updates on the management of acute myeloid leukemia

Revista: CANCERS

ISSN: 2072-6694 Vol.14 N° 19 2022 págs. 4756

Resumen

Simple Summary Acute myeloid leukemia is the most common type of acute leukemia in adults. It is associated with poor outcomes, especially in older patients. Treatments based exclusively on chemotherapy do not achieve high overall survival rates, or in any case, only in a small group of patients. The objective of this review is to discuss the treatment of acute myeloid leukemia from newly approved therapeutic drugs to newer strategies. In first line, the combination of new targeted therapies with standard chemotherapy achieves better outcomes in "fit" patients. For "unfit" patients the combination of different targeted therapies provides them with better overall survival rates, with limited toxicity. As for refractory and relapsed acute myeloid leukemia, development of immunotherapy or new targeted therapies brings new hope. Acute myeloid leukemia is a heterogeneous disease defined by a large spectrum of genetic aberrations that are potential therapeutic targets. New targeted therapies have changed the landscape for a disease with poor outcomes. They are more effective than standard chemotherapy with a good safety profile. For "fit patients" in first-line, the combination of gemtuzumab ozogamicin or midostaurin with intensive chemotherapy or Vyxeos is now considered the "standard of care" for selected patients. On the other hand, for "unfit patients", azacitidine-venetoclax has been consolidated as a frontline treatment, while other combinations with magrolimab or ivosidenib are in development. Nevertheless, global survival results, especially in relapsed or refractory patients, remain unfavorable. New immunotherapies or targeted therapies, such as Menin inhibitors or sabatolimab, represent an opportunity in this situation. Future directions will probably come from combinations of different targeted therapies ("triplets") and maintenance strategies guided by measurable residual disease.
Autores: Guedan, S.; Luu, M.; Ammar, D.; et al.

Título: Time 2EVOLVE: predicting efficacy of engineered T-cells - how far is the bench from the bedside?

Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER

ISSN: 2051-1426 Vol.10 N° 5 2022 págs. e003487

Resumen

Immunotherapy with gene engineered CAR and TCR transgenic T-cells is a transformative treatment in cancer medicine. There is a rich pipeline with target antigens and sophisticated technologies that will enable establishing this novel treatment not only in rare hematological malignancies, but also in common solid tumors. The T2EVOLVE consortium is a public private partnership directed at accelerating the preclinical development of and increasing access to engineered T-cell immunotherapies for cancer patients. A key ambition in T2EVOLVE is to assess the currently available preclinical models for evaluating safety and efficacy of engineered T cell therapy and developing new models and test parameters with higher predictive value for clinical safety and efficacy in order to improve and accelerate the selection of lead T-cell products for clinical translation. Here, we review existing and emerging preclinical models that permit assessing CAR and TCR signaling and antigen binding, the access and function of engineered T-cells to primary and metastatic tumor ligands, as well as the impact of endogenous factors such as the host immune system and microbiome. Collectively, this review article presents a perspective on an accelerated translational development path that is based on innovative standardized preclinical test systems for CAR and TCR transgenic T-cell products.
Autores: McLornan, D. P. (Autor de correspondencia); Gras, L.; Martin, I.; et al.

Título: Outcome of allogeneic haematopoietic cell transplantation in eosinophilic disorders: a retrospective study by the chronic malignancies working party of the EBMT

Revista: BRITISH JOURNAL OF HAEMATOLOGY

ISSN: 0007-1048 Vol.198 N° 1 2022 págs. 209 - 213
Autores: Amundarain, A.; Valcárcel, L. V.; Ordóñez Ciriza, Raquel; et al.

Título: Landscape and clinical significance of long noncoding RNAs involved in multiple myeloma expressed fusion transcripts

Revista: AMERICAN JOURNAL OF HEMATOLOGY

ISSN: 0361-8609 Vol.97 N° 3 2022 págs. E113 - E117
Autores: Vilarrasa-Blasi, R. (Autor de correspondencia); Verdaguer-Dot, N.; Belver, L.; et al.

Título: Insights into the mechanisms underlying aberrant SOX11 oncogene expression in mantle cell lymphoma

Revista: LEUKEMIA

ISSN: 0887-6924 Vol.36 N° 2 2022 págs. 583 - 587
Autores: Ghobrial, I. M. (Autor de correspondencia); Rodríguez Otero, Paula; Koh, Y.; et al.

Título: P-137: ITHACA, a randomized multicenter phase 3 study of Isatuximab in combination with Lenalidomide and Dexamethasone in high-risk smoldering Multiple Myeloma: safety run-in preliminary results (vol 21, pg S109, 2021)

Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA

ISSN: 2152-2650 Vol.22 N° 7 2022 págs. 545
Autores: Peng, J.; SERRANO SANZ, Guillermo; Traniello, I. M.; et al.

Título: SimiC enables the inference of complex gene regulatory dynamics across cell phenotypes

Revista: COMMUNICATIONS BIOLOGY

ISSN: 2399-3642 Vol.5 N° 1 2022 págs. 351

Resumen

Single-cell RNA-Sequencing has the potential to provide deep biological insights by revealing complex regulatory interactions across diverse cell phenotypes at single-cell resolution. However, current single-cell gene regulatory network inference methods produce a single regulatory network per input dataset, limiting their capability to uncover complex regulatory relationships across related cell phenotypes. We present SimiC, a single-cell gene regulatory inference framework that overcomes this limitation by jointly inferring distinct, but related, gene regulatory dynamics per phenotype. We show that SimiC uncovers key regulatory dynamics missed by previously proposed methods across a range of systems, both model and non-model alike. In particular, SimiC was able to uncover CAR T cell dynamics after tumor recognition and key regulatory patterns on a regenerating liver, and was able to implicate glial cells in the generation of distinct behavioral states in honeybees. SimiC hence establishes a new approach to quantitating regulatory architectures between distinct cellular phenotypes, with far-reaching implications for systems biology.
Autores: DePasquale, E. A. K.; Ssozi, D.; Ainciburu Fernandez, Marina; et al.

Título: Single-cell multiomics reveals clonal T-Cell expansions and exhaustion in blastic plasmacytoid dendritic cell neoplasm

Revista: FRONTIERS IN IMMUNOLOGY

ISSN: 1664-3224 Vol.13 2022 págs. 809414

Resumen

The immune system represents a major barrier to cancer progression, driving the evolution of immunoregulatory interactions between malignant cells and T-cells in the tumor environment. Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare acute leukemia with plasmacytoid dendritic cell (pDC) differentiation, provides a unique opportunity to study these interactions. pDCs are key producers of interferon alpha (IFNA) that play an important role in T-cell activation at the interface between the innate and adaptive immune system. To assess how uncontrolled proliferation of malignant BPDCN cells affects the tumor environment, we catalog immune cell heterogeneity in the bone marrow (BM) of five healthy controls and five BPDCN patients by analyzing 52,803 single-cell transcriptomes, including 18,779 T-cells. We test computational techniques for robust cell type classification and find that T-cells in BPDCN patients consistently upregulate interferon alpha (IFNA) response and downregulate tumor necrosis factor alpha (TNFA) pathways. Integrating transcriptional data with T-cell receptor sequencing via shared barcodes reveals significant T-cell exhaustion in BPDCN that is positively correlated with T-cell clonotype expansion. By highlighting new mechanisms of T-cell exhaustion and immune evasion in BPDCN, our results demonstrate the value of single-cell multiomics to understand immune cell interactions in the tumor environment.
Autores: Dorr, D.; Obermayer, B.; Weiner, J. M.; et al.

Título: C/EBPß regulates lipid metabolism and Pparg isoform 2 expression in alveolar macrophages

Revista: SCIENCE IMMUNOLOGY

ISSN: 2470-9468 Vol.7 N° 75 2022 págs. eabj0140

Resumen

Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by accumulation of surfactant lipoproteins within the lung alveoli. Alveolar macrophages (AMs) are crucial for surfactant clearance, and their differentiation depends on colony-stimulating factor 2 (CSF2), which regulates the establishment of an AM-characteristic gene regulatory network. Here, we report that the transcription factor CCAAT/enhancer binding protein ss (C/EBP ss) is essential for the development of the AM identity, as demonstrated by transcriptome and chromatin accessibility analysis. Furthermore, C/EBP ss-deficient AMs showed severe defects in proliferation, phagocytosis, and lipid metabolism, collectively resulting in a PAP-like syndrome. Mechanistically, the long C/EBP ss protein variants LAP* and LAP together with CSF2 signaling induced the expression of Pparg isoform 2 but not Pparg isoform 1, a molecular regulatory mechanism that was also observed in other CSF2-primed macrophages. These results uncover C/EBP ss as a key regulator of AM cell fate and shed light on the molecular networks controlling lipid metabolism in macrophages.
Autores: Viñado, A. C.; Calvo Arnedo, Isabel; Cenzano Armendariz, Itziar; et al.

Título: The bone marrow niche regulates redox and energy balance in MLL::AF9 leukemia stem cells

Revista: LEUKEMIA

ISSN: 0887-6924 Vol.36 N° 8 2022 págs. 1969 - 1979

Resumen

Eradicating leukemia requires a deep understanding of the interaction between leukemic cells and their protective microenvironment. The CXCL12/CXCR4 axis has been postulated as a critical pathway dictating leukemia stem cell (LSC) chemoresistance in AML due to its role in controlling cellular egress from the marrow. Nevertheless, the cellular source of CXCL12 in the acute myeloid leukemia (AML) microenvironment and the mechanism by which CXCL12 exerts its protective role in vivo remain unresolved. Here, we show that CXCL12 produced by Prx1+ mesenchymal cells but not by mature osteolineage cells provide the necessary cues for the maintenance of LSCs in the marrow of an MLL::AF9-induced AML model. Prx1+ cells promote survival of LSCs by modulating energy metabolism and the REDOX balance in LSCs. Deletion of Cxcl12 leads to the accumulation of reactive oxygen species and DNA damage in LSCs, impairing their ability to perpetuate leukemia in transplantation experiments, a defect that can be attenuated by antioxidant therapy. Importantly, our data suggest that this phenomenon appears to be conserved in human patients. Hence, we have identified Prx1+ mesenchymal cells as an integral part of the complex niche-AML metabolic intertwining, pointing towards CXCL12/CXCR4 as a target to eradicate parenchymal LSCs in AML.
Autores: Ainciburu Fernandez, Marina; Berastegui Zufiaurre, Nerea; Romero Riojas, Juan Pablo; et al.

Título: The transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes

Revista: NATURE COMMUNICATIONS

ISSN: 2041-1723 Vol.13 N° 1 2022 págs. 7619

Resumen

Myelodysplastic syndromes (MDS) are hematopoietic stem cell (HSC) malignancies characterized by ineffective hematopoiesis, with increased incidence in older individuals. Here we analyze the transcriptome of human HSCs purified from young and older healthy adults, as well as MDS patients, identifying transcriptional alterations following different patterns of expression. While aging-associated lesions seem to predispose HSCs to myeloid transformation, disease-specific alterations may trigger MDS development. Among MDS-specific lesions, we detect the upregulation of the transcription factor DNA Damage Inducible Transcript 3 (DDIT3). Overexpression of DDIT3 in human healthy HSCs induces an MDS-like transcriptional state, and dyserythropoiesis, an effect associated with a failure in the activation of transcriptional programs required for normal erythroid differentiation. Moreover, DDIT3 knockdown in CD34+ cells from MDS patients with anemia is able to restore erythropoiesis. These results identify DDIT3 as a driver of dyserythropoiesis, and a potential therapeutic target to restore the inefficient erythroid differentiation characterizing MDS patients. © 2022, The Author(s).
Autores: Moreira-Silva, F.; Outeiro-Pinho, G.; Lobo, J.; et al.

Título: G9a inhibition by CM-272: developing a novel anti-tumoral strategy for castration-resistant prostate cancer using 2D and 3D in vitro models

Revista: BIOMEDICINE AND PHARMACOTHERAPY

ISSN: 0753-3322 Vol.150 2022 págs. 113031

Resumen

Castration-resistant prostate cancer (CRPC) is an incurable form of prostate cancer (PCa), with DNMT1 and G9a being reported as overexpressed, rendering them highly attractive targets for precision medicine. CM-272 is a dual inhibitor of both methyltransferases' activity. Herein, we assessed the response of different PCa cell lines to CM-272, in both 2D and 3D models, and explored the molecular mechanisms underlying CM-272 inhibitory effects.CRPC tissues displayed significantly higher DNMT1, G9a and H3K9me2 expression than localized PCa. In vitro, CM-272 caused a significant decrease in PCa cell viability and proliferation alongside with increased apoptotic levels. We disclose that, under the evaluated dose, CM-272 led to G9a activity inhibition, while not significantly affecting DNMT1 activity. Upon G9a knockdown, DU145 and PC3 showed decreased cell viability. Remarkably, DU145 cells treated with CM-272 or with G9a knockdown displayed no differences in viability, suggesting a SET dependent mechanism. Contrarily, PC3 cell viability impact was higher in G9a knockdown, compared with CM 272 treatment, suggesting an additional G9a function. Moreover, DU145 cells overexpressing catalytically functional G9a disclosed higher resistance to CM-272 treatment, reinforcing that the drug mechanism of action is dependent on G9a catalytic function.Importantly, we successfully assembled spheroids from several prostate cell lines. Our results showed that CM 272 retained its anti-tumoral effects in 3D PCa models, leading to a clear reduction in cancer cell survival. We concluded that inhibition of G9a methyltransferase activity by CM-272 has anti-tumor effect in PCa cells, holding therapeutic potential against CRPC.
Autores: Gimeno, M.; San José Enériz, Edurne; Rubio Díaz-Cordoves, Ángel; et al.

Título: Identifying lethal dependencies with HUGE predictive power

Revista: CANCERS

ISSN: 2072-6694 Vol.14 N° 13 2022 págs. 3251

Resumen

Simple Summary This work shows that the predictions of lethal dependencies (LEDs) between genes can be dramatically improved by incorporating the "HUb effect in Genetic Essentiality" (HUGE) of gene alterations. In three genome-wide loss-of-function screens-Project Score, CERES score and DEMETER score-LEDs are identified with 75 times larger statistical power than using state-of-the-art methods. In AML, we identified LEDs not recalled by previous pipelines, including FLT3-mutant genotypes sensitive to FLT3 inhibitors. Interestingly, in-vitro validations confirm lethal de-pendencies of either NRAS or PTPN11 depending on the NRAS mutational status. Recent functional genomic screens-such as CRISPR-Cas9 or RNAi screening-have fostered a new wave of targeted treatments based on the concept of synthetic lethality. These approaches identified LEthal Dependencies (LEDs) by estimating the effect of genetic events on cell viability. The multiple-hypothesis problem is related to a large number of gene knockouts limiting the statistical power of these studies. Here, we show that predictions of LEDs from functional screens can be dramatically improved by incorporating the "HUb effect in Genetic Essentiality" (HUGE) of gene alterations. We analyze three recent genome-wide loss-of-function screens-Project Score, CERES score and DEMETER score-identifying LEDs with 75 times larger statistical power than using state-of-the-art methods. Using acute myeloid leukemia, breast cancer, lung adenocarcinoma and colon adenocarcinoma as disease models, we validate that our predictions are enriched in a recent harmonized knowledge base of clinical interpretations of somatic genomic variants in cancer (AUROC > 0.87). Our approach is effective even in tumors with large genetic heterogeneity such as acute myeloid leukemia, where we identified LEDs not recalled by previous pipelines, including FLT3-mutant genotypes sensitive to FLT3 inhibitors. Interestingly, in-vitro validations confirm lethal dependencies of either NRAS or PTPN11 depending on the NRAS mutational status. HUGE will hopefully help discover novel genetic dependencies amenable for precision-targeted therapies in cancer. All the graphs showing lethal dependencies for the 19 tumor types analyzed can be visualized in an interactive tool.
Autores: Armes, H.; Bewicke-Copley, F.; Rio-Machin, A.; et al.

Título: Germline ERCC excision repair 6 like 2 (ERCC6L2) mutations lead to impaired erythropoiesis and reshaping of the bone marrow microenvironment

Revista: BRITISH JOURNAL OF HAEMATOLOGY

ISSN: 0007-1048 Vol.199 N° 5 2022 págs. 754 - 764

Resumen

Despite the inclusion of inherited myeloid malignancies as a separate entity in the World Health Organization Classification, many established predisposing loci continue to lack functional characterization. While germline mutations in the DNA repair factor ERCC excision repair 6 like 2 (ERCC6L2) give rise to bone marrow failure and acute myeloid leukaemia, their consequences on normal haematopoiesis remain unclear. To functionally characterise the dual impact of germline ERCC6L2 loss on human primary haematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs), we challenged ERCC6L2-silenced and patient-derived cells ex vivo. Here, we show for the first time that ERCC6L2-deficiency in HSPCs significantly impedes their clonogenic potential and leads to delayed erythroid differentiation. This observation was confirmed by CIBERSORTx RNA-sequencing deconvolution performed on ERCC6L2-silenced erythroid-committed cells, which demonstrated higher proportions of polychromatic erythroblasts and reduced orthochromatic erythroblasts versus controls. In parallel, we demonstrate that the consequences of ERCC6L2-deficiency are not limited to HSPCs, as we observe a striking phenotype in patient-derived and ERCC6L2-silenced MSCs, which exhibit enhanced osteogenesis and suppressed adipogenesis. Altogether, our study introduces a valuable surrogate model to study the impact of inherited myeloid mutations and highlights the importance of accounting for the influence of germline mutations in HSPCs and their microenvironment.
Autores: Garreta, E.; Prado, P.; Stanifer, M. L.; et al.

Título: A diabetic milieu increases ACE2 expression and cellular susceptibility to SARS-CoV-2 infections in human kidney organoids and patient cells

Revista: CELL METABOLISM

ISSN: 1550-4131 Vol.34 N° 6 2022 págs. 857 - 873.e9

Resumen

It is not well understood why diabetic individuals are more prone to develop severe COVID-19. To this, we here established a human kidney organoid model promoting early hallmarks of diabetic kidney disease development. Upon SARS-CoV-2 infection, diabetic-like kidney organoids exhibited higher viral loads compared with their control counterparts. Genetic deletion of the angiotensin-converting enzyme 2 (ACE2) in kidney organoids under control or diabetic-like conditions prevented viral detection. Moreover, cells isolated from kidney biopsies from diabetic patients exhibited altered mitochondrial respiration and enhanced glycolysis, resulting in higher SARS-CoV-2 infections compared with non-diabetic cells. Conversely, the exposure of patient cells to dichloroacetate (DCA), an inhibitor of aerobic glycolysis, resulted in reduced SARS-CoV-2 infections. Our results provide insights into the identification of diabetic-induced metabolic programming in the kidney as a critical event increasing SARS-CoV-2 infection susceptibility, opening the door to the identification of new interventions in COVID-19 pathogenesis targeting energy metabolism.
Autores: Colyn, L.; Álvarez-Sola, G.; Latasa Sada, María Ujué; et al.

Título: New molecular mechanisms in cholangiocarcinoma: signals triggering interleukin-6 production in tumor cells and KRAS co-opted epigenetic mediators driving metabolic reprogramming

Revista: JOURNAL OF EXPERIMENTAL AND CLINICAL CANCER RESEARCH

ISSN: 1756-9966 Vol.41 N° 1 2022 págs. 183

Resumen

Background Cholangiocarcinoma (CCA) is still a deadly tumour. Histological and molecular aspects of thioacetamide (TAA)-induced intrahepatic CCA (iCCA) in rats mimic those of human iCCA. Carcinogenic changes and therapeutic vulnerabilities in CCA may be captured by molecular investigations in bile, where we performed bile proteomic and metabolomic analyses that help discovery yet unknown pathways relevant to human iCCA. Methods Cholangiocarcinogenesis was induced in rats (TAA) and mice (Jnk(Delta hepa) + CCl4 + DEN model). We performed proteomic and metabolomic analyses in bile from control and CCA-bearing rats. Differential expression was validated in rat and human CCAs. Mechanisms were addressed in human CCA cells, including Huh28-KRAS(G12D) cells. Cell signaling, growth, gene regulation and [U-C-13]-D-glucose-serine fluxomics analyses were performed. In vivo studies were performed in the clinically-relevant iCCA mouse model. Results Pathways related to inflammation, oxidative stress and glucose metabolism were identified by proteomic analysis. Oxidative stress and high amounts of the oncogenesis-supporting amino acids serine and glycine were discovered by metabolomic studies. Most relevant hits were confirmed in rat and human CCAs (TCGA). Activation of interleukin-6 (IL6) and epidermal growth factor receptor (EGFR) pathways, and key genes in cancer-related glucose metabolic reprogramming, were validated in TAA-CCAs. In TAA-CCAs, G9a, an epigenetic pro-tumorigenic writer, was also increased. We show that EGFR signaling and mutant KRAS(G12D) can both activate IL6 production in CCA cells. Furthermore, phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in serine-glycine pathway, was upregulated in human iCCA correlating with G9a expression. In a G9a activity-dependent manner, KRAS(G12D) promoted PHGDH expression, glucose flow towards serine synthesis, and increased CCA cell viability. KRAS(G12D) CAA cells were more sensitive to PHGDH and G9a inhibition than controls. In mouse iCCA, G9a pharmacological targeting reduced PHGDH expression. Conclusions In CCA, we identified new pro-tumorigenic mechanisms: Activation of EGFR signaling or KRAS mutation drives IL6 expression in tumour cells; Glucose metabolism reprogramming in iCCA includes activation of the serine-glycine pathway; Mutant KRAS drives PHGDH expression in a G9a-dependent manner; PHGDH and G9a emerge as therapeutic targets in iCCA.
Autores: Poza-Viejo, L.; Paya-Milans, M.; San Martín Úriz, Patxi; et al.

Título: Conserved and distinct roles of H3K27me3 demethylases regulating flowering time in Brassica rapa

Revista: PLANT CELL AND ENVIRONMENT

ISSN: 0140-7791 Vol.45 N° 5 2022 págs. 1428 - 1441

Resumen

Epigenetic regulation is necessary for optimal organism development and preservation of gene expression profiles in the cell. In plants, the trimethylation of histone H3 lysine 27 (H3K27me3) is a silencing epigenetic mark relevant for developmental transitions like flowering. The floral transition is a key agronomic trait; however, the epigenetic mechanisms of flowering time regulation in crops remain poorly understood. Here we study the Jumonji H3K27me3 demethylases BraA.REF6 and BraA.ELF6 in Brassica rapa. Phenotypic characterization of novel mutant lines and genome-wide H3K27me3 chromatin immunoprecipitation and transcriptomic analyses indicated that BraA.REF6 plays a greater role than BraA.ELF6 in fine-tuning H3K27me3 levels. In addition, we found that braA.elf6 mutants were early flowering due to high H3K27me3 levels at B. rapa homologs of the floral repressor FLC. Unlike mutations in Arabidopsis thaliana, braA.ref6 mutants were late flowering without altering the expression of B. rapa FLC genes. Remarkably, we found that BraA.REF6 regulated a number of gibberellic acid (GA) biosynthetic genes, including a homolog of GA1, and that GA-treatment complemented the late flowering mutant phenotype. This study increases our understanding of the epigenetic regulation of flowering time in B. rapa, highlighting conserved and distinct regulatory mechanisms between model and crop species.
Autores: Rodríguez Márquez, Paula; Calleja Cervantes, María Erendira; SERRANO SANZ, Guillermo; et al.

Título: CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome

Revista: SCIENCE ADVANCES

ISSN: 2375-2548 Vol.8 N° 39 2022 págs. eabo0514

Resumen

Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study, we address the impact of CAR density on the functionality of BCMA CAR T cells. Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with up-regulation of exhaustion markers and increased in vitro cytotoxicity but a decrease in in vivo BM infiltration. Characterization of gene regulatory networks using scRNA-seq identified regulons associated to activation and exhaustion up-regulated in CARHigh T cells, providing mechanistic insights behind differential functionality of these cells. Last, we demonstrate that patients treated with CAR T cell products enriched in CARHigh T cells show a significantly worse clinical response in several hematological malignancies. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with notable impact on clinical response.
Autores: Ye, J. ; Calvo Arnedo, Isabel; Cenzano Armendariz, Itziar; et al.

Título: Deconvolution of the hematopoietic stem cell microenvironment reveals a high degree of specialization and conservation

Revista: ISCIENCE

ISSN: 2589-0042 Vol.25 N° 5 2022 págs. 104225

Resumen

Understanding the regulation of normal and malignant human hematopoiesis requires comprehensive cell atlas of the hematopoietic stem cell (HSC) regulatory microenvironment. Here, we develop a tailored bioinformatic pipeline to integrate public and proprietary single-cell RNA sequencing (scRNA-seq) datasets. As a result, we robustly identify for the first time 14 intermediate cell states and 11 stages of differentiation in the endothelial and mesenchymal BM compartments, respectively. Our data provide the most comprehensive description to date of the murine HSC-regulatory microenvironment and suggest a higher level of specialization of the cellular circuits than previously anticipated. Furthermore, this deep characterization allows inferring conserved features in human, suggesting that the layers of microenvironmental regulation of hematopoiesis may also be shared between species. Our resource and methodology is a stepping-stone toward a comprehensive cell atlas of the BM microenvironment.
Autores: Martínez Turrillas, Rebeca; Martin Mallo, Angel; Rodríguez Díaz, Saray; et al.

Título: In vivo CRISPR-Cas9 inhibition of hepatic LDH as treatment of primary hyperoxaluria

Revista: MOLECULAR THERAPY. METHODS & CLINICAL DEVELOPMENT

ISSN: 2329-0501 Vol.25 2022 págs. 137 - 146

Resumen

Genome-editing strategies, especially CRISPR-Cas9 systems, have substantially increased the efficiency of innovative therapeutic approaches for monogenic diseases such as primary hyperoxalurias (PHs). We have previously demonstrated that inhibition of glycolate oxidase using CRISPR-Cas9 systems represents a promising therapeutic option for PH type I (PH1). Here, we extended our work evaluating the efficacy of liver-specific inhibition of lactate dehydrogenase (LDH), a key enzyme responsible for converting glyoxylate to oxalate; this strategy would not be limited to PH1, being applicable to other PH subtypes. In this work, we demonstrate a liver-specific inhibition of LDH that resulted in a drastic reduction of LDH levels in the liver of PH1 and PH3 mice after a single-dose delivery of AAV8 vectors expressing the CRISPR-Cas9 system, resulting in reduced urine oxalate levels and kidney damage without signs of toxicity. Deep sequencing analysis revealed that this approach was safe and specific, with no off-targets detected in the liver of treated animals and no on-target/off-tissue events. Altogether, our data provide evidence that in vivo genome editing using CRISPR-Cas9 systems would represent a valuable tool for improved therapeutic approaches for PH.
Autores: Ainciburu Fernandez, Marina; Morgan, D. M.; De Pasquale, E. A. K.; et al.

Título: WAT3R: recovery of T-cell receptor variable regions from 3 ' single-cell RNA-sequencing

Revista: BIOINFORMATICS

ISSN: 1367-4803 Vol.38 N° 14 2022 págs. 3645 - 3647

Resumen

Diversity of the T-cell receptor (TCR) repertoire is central to adaptive immunity. The TCR is composed of alpha and beta chains, encoded by the TRA and TRB genes, of which the variable regions determine antigen specificity. To generate novel biological insights into the complex functioning of immune cells, combined capture of variable regions and single-cell transcriptomes provides a compelling approach. Recent developments enable the enrichment of TRA and TRB variable regions from widely used technologies for 3'-based single-cell RNA-sequencing (scRNA-seq). However, a comprehensive computational pipeline to process TCR-enriched data from 3' scRNA-seq is not available. Here, we present an analysis pipeline to process TCR variable regions enriched from 3' scRNA-seq cDNA. The tool reports TRA and TRB nucleotide and amino acid sequences linked to cell barcodes, enabling the reconstruction of T-cell clonotypes with associated transcriptomes. We demonstrate the software using peripheral blood mononuclear cells from a healthy donor and detect TCR sequences in a high proportion of single T cells. Detection of TCR sequences is low in non-T-cell populations, demonstrating specificity. Finally, we show that TCR clones are larger in CD8 Memory T cells than in other T-cell types, indicating an association between T-cell clonotypes and differentiation states.
Autores: Ayala, R.; Carreno-Tarragona, G.; Barragan, E.; et al.

Título: Impact of FLT3-ITD mutation status and its ratio in a cohort of 2901 patients undergoing upfront intensive chemotherapy: a PETHEMA registry study

Revista: CANCERS

ISSN: 2072-6694 Vol.14 N° 23 2022 págs. 5799

Resumen

Simple Summary The prognostic impact of FLT3-ITD allele ratio (AR) is a matter of controversy. We analyzed 2901 AML patients with long-term follow-up treated with PETHEMA protocols in the pre-FLT3 inhibitors era, with 579 of them harboring the FLT3-ITD mutation. We found that FLT3-ITD AR > 0.5 was associated with lower complete remission and rate and overall survival, while AR > 0.8 was associated with lower RFS. An AR of 0.44 was the best cutoff for OS and 0.8 for RFS. Overall, allo- and auto-hematopoietic stem cell transplant (HSCT) in first CR offered similar OS in patients with AR < 0.44, while allo-HSCT improved OS for those with higher AR. However, allo-HSCT resulted in better OS and RFS as compared to auto-HSCT in NPM1/FLT3-ITD-mutated AML regardless of pre-established AR cutoff (<= 0.5 vs. >0.5), supporting the use of other risk stratification tools, such as NPM1 MRD monitoring, in this setting. FLT3-ITD results in a poor prognosis in terms of overall survival (OS) and relapse-free survival (RFS) in acute myeloid leukemia (AML). However, the prognostic usefulness of the allelic ratio (AR) to select post-remission therapy remains controversial. Our study focuses on the prognostic impact of FLT3-ITD and its ratio in a series of 2901 adult patients treated intensively in the pre-FLT3 inhibitor era and reported in the PETHEMA registry. A total of 579 of these patients (20%) harbored FLT3-ITD mutations. In multivariate analyses, patients with an FLT3-ITD allele ratio (AR) of >0.5 showed a lower complete remission (CR rate) and OS (HR 1.47, p = 0.009), while AR > 0.8 was associated with poorer RFS (HR 2.1; p < 0.001). Among NPM1/FLT3-ITD-mutated patients, median OS gradually decreased according to FLT3-ITD status and ratio (34.3 months FLT3-ITD-negative, 25.3 months up to 0.25, 14.5 months up to 0.5, and 10 months >= 0.5, p < 0.001). Post-remission allogeneic transplant (allo-HSCT) resulted in better OS and RFS as compared to auto-HSCT in NPM1/FLT3-ITD-mutated AML regardless of pre-established AR cutoff (<= 0.5 vs. >0.5). Using the maximally selected log-rank statistics, we established an optimal cutoff of FLT3-ITD AR of 0.44 for OS, and 0.8 for RFS. We analyzed the OS and RFS according to FLT3-ITD status in all patients, and we found that the group of FLT3-ITD-positive patients with AR < 0.44 had similar 5-year OS after allo-HSCT or auto-HSCT (52% and 41%, respectively, p = 0.86), but worse RFS after auto-HSCT (p = 0.01). Among patients with FLT3-ITD AR > 0.44, allo-HSCT was superior to auto-HSCT in terms of OS and RFS. This study provides more evidence for a better characterization of patients with AML harboring FLT3-ITD mutations.
Autores: Saumell, S.; Fernández-Serrano, M.; Mesa, A.; et al.

Título: Prognostic impact of micromegakaryocytes in primary myelodysplastic syndromes

Revista: LEUKEMIA AND LYMPHOMA

ISSN: 1042-8194 Vol.63 N° 5 2022 págs. 1227 - 1235

Resumen

Micromegakaryocytes (microMKs) are considered a myelodysplastic feature of myeloid neoplasms in adults, with an adverse prognosis connotation. However, this notion in MDS has not been well proved. In our cohort of 287 MDS, patients with microMKs showed lower overall survival (OS) (HR, 2.12; 95% CI, 1.47-3.06; p = 0.000036) and higher risk of acute myeloid leukemia (AML) evolution (HR, 4.8; 95% CI, 2.9-11.01; p = 0.00021). Results were validated with an independent cohort. In multivariate analysis, the presence of microMKs maintained its independent association with OS (HR, 1.54, 95% CI, 1.13-2.1, p = 0.0059) and AML transformation (HR, 2.28, 95% CI, 1.2-4.4, p = 0.014). Moreover, by adding 1 point to the IPSS-R score in patients with microMKs, we improved the IPSS-R accuracy. Interestingly, adding that 1-point, 29% of intermediate IPSS-R risk group patients were upgraded to the high-risk group. In summary, we confirmed that the presence of microMKs implies worse outcomes in MDS and suggested a modification improving IPSS-R.
Autores: Palacios, M.; Giménez, Y.; Peral, J.; et al.

Título: Development of a gene editing approach for the treatment of RPL5-deficient Diamond-Blackfan anemia patients

Revista: HUMAN GENE THERAPY

ISSN: 1043-0342 Vol.33 N° 23-24 2022 págs. A154 - A154
Autores: Díez, B.; Calviño Sampedro, Cristina; Fernández-García, M.; et al.

Título: Development of transposon-based CAR-T cells for the treatment of patients with lymphoma

Revista: HUMAN GENE THERAPY

ISSN: 1043-0342 Vol.33 N° 23-24 2022 págs. A126 - A127
Autores: Redondo, S.; García-Cadenas, I.; Cuesta, M.; et al.

Título: Low rate of documented infections as the cause of enterocolitis in allogeneic stem cell transplant recipients: Prospective study by the geth

Revista: BONE MARROW TRANSPLANTATION

ISSN: 0268-3369 Vol.57 N° SUPPL 1 2022 págs. 276 - 276
Autores: Broijl, A.; Van De Donk, N. W. C. J.; Bosch, F.; et al.

Título: Phase I dose escalation of LAVA-051, a novel bispecific gamma-delta T-cell engager (Gammabody), in relapsed/refractory hematological malignancies

Revista: JOURNAL OF CLINICAL ONCOLOGY

ISSN: 0732-183X Vol.40 N° 16 2022
Autores: Zapata-Linares, N.; Toillon, I.; Wanherdrick, K.; et al.

Título: Implication of bone marrow adipose tissue in bone homeostasis during osteoarthritis

Revista: OSTEOARTHRITIS AND CARTILAGE

ISSN: 1063-4584 Vol.30 N° Supl. 1 2022 págs. S303
Autores: Pérez-Martínez, A.; Belendez-Bieler, C.; Molina-Angulo, B.; et al.

Título: Treosulfan-based conditioning regimen in hematopoietic stem cell transplantation in children and adolescents: An analysis of spanish group of hematopoietic stem cell transplantation (GETH)

Revista: BONE MARROW TRANSPLANTATION

ISSN: 0268-3369 Vol.57 N° SUPPL 1 2022 págs. 372 - 372
Autores: Carrasco Leon, Arantxa; Amundarain, A.; Gomez Echarte, Nahia; et al.

Título: The Role of lncRNAs in the Pathobiology and Clinical Behavior of Multiple Myeloma

Revista: CANCERS

ISSN: 2072-6694 Vol.13 N° 8 2021 págs. 1976

Resumen

Simple Summary Multiple myeloma (MM), the second most common hematological neoplasm, is still considered an incurable disease. Long non-coding RNAs (lncRNAs), genes that do not encode proteins, participate in numerous biological processes, but their deregulation, like that of coding genes, can contribute to carcinogenesis. Increasing evidence points to the relevant role of lncRNAs in the development of human tumors, such that they emerge as attractive biomarkers and therapeutic targets for cancer treatment, including MM. Here we review the oncogenic or tumor-suppressor functions of lncRNAs in MM and provide an overview of novel therapeutic approaches based on lncRNAs that will help to improve the management of these patients. MM is a hematological neoplasm that is still considered an incurable disease. Besides established genetic alterations, recent studies have shown that MM pathogenesis is also characterized by epigenetic aberrations, such as the gain of de novo active chromatin marks in promoter and enhancer regions and extensive DNA hypomethylation of intergenic regions, highlighting the relevance of these non-coding genomic regions. A recent study described how long non-coding RNAs (lncRNAs) correspond to 82% of the MM transcriptome and an increasing number of studies have demonstrated the importance of deregulation of lncRNAs in MM. In this review we focus on the deregulated lncRNAs in MM, including their biological or functional mechanisms, their role as biomarkers to improve the prognosis and monitoring of MM patients, and their participation in drug resistance. Furthermore, we also discuss the evidence supporting the role of lncRNAs as therapeutic targets through different novel RNA-based strategies.
Autores: Palacios-Berraquero, M. L.; Alfonso Piérola, Ana (Autor de correspondencia)

Título: Current therapy of the patients with MDS: walking towards personalized therapy

Revista: JOURNAL OF CLINICAL MEDICINE

ISSN: 2077-0383 Vol.10 N° 10 2021 págs. 2107

Resumen

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, dysplasia and peripheral cytopenias. Nowadays, MDS therapy is selected based on risk. The goals of therapy are different in low-risk and high-risk patients. In low-risk MDS, the goal is to decrease transfusion needs and to increase the quality of life. Currently, available drugs for newly diagnosed low-risk MDS include growth factor support, lenalidomide and immunosuppressive therapy. Additionally, luspatercept has recently been added to treat patients with MDS with ring sideroblasts, who are not candidates or have lost the response to erythropoiesis-stimulating agents. Treatment of high-risk patients is aimed to improve survival. To date, the only currently approved treatments are hypomethylating agents and allogeneic stem cell transplantation. However, the future for MDS patients is promising. In recent years, we are witnessing the emergence of multiple treatment combinations based on hypomethylating agents (pevonedistat, magrolimab, eprenetapopt, venetoclax) that have proven to be effective in MDS, even those with high-risk factors. Furthermore, the approval in the US of an oral hypomethylating agent opens the door to exclusively oral combinations for these patients and their consequent impact on the quality of life of these patients. Relapsed and refractory patients remain an unmet clinical need. We need more drugs and clinical trials for this profile of patients who have a dismal prognosis.
Autores: Maes, K. (Autor de correspondencia); Mondino, A.; Lasarte Sagastibelza, Juan José; et al.

Título: Epigenetic modifiers: anti-neoplastic drugs with immunomodulating potential

Revista: FRONTIERS IN IMMUNOLOGY

ISSN: 1664-3224 Vol.12 2021 págs. 652160

Resumen

Cancer cells are under the surveillance of the host immune system. Nevertheless, a number of immunosuppressive mechanisms allow tumors to escape protective responses and impose immune tolerance. Epigenetic alterations are central to cancer cell biology and cancer immune evasion. Accordingly, epigenetic modulating agents (EMAs) are being exploited as anti-neoplastic and immunomodulatory agents to restore immunological fitness. By simultaneously acting on cancer cells, e.g. by changing expression of tumor antigens, immune checkpoints, chemokines or innate defense pathways, and on immune cells, e.g. by remodeling the tumor stroma or enhancing effector cell functionality, EMAs can indeed overcome peripheral tolerance to transformed cells. Therefore, combinations of EMAs with chemo- or immunotherapy have become interesting strategies to fight cancer. Here we review several examples of epigenetic changes critical for immune cell functions and tumor-immune evasion and of the use of EMAs in promoting anti-tumor immunity. Finally, we provide our perspective on how EMAs could represent a game changer for combinatorial therapies and the clinical management of cancer.
Autores: Cuenca, I. ; Alameda Serrano, Daniel; Sánchez, B.; et al.

Título: Immunogenetic characterization of clonal plasma cells in systemic light-chain amyloidosis

Revista: LEUKEMIA

ISSN: 0887-6924 Vol.35 N° 1 2021 págs. 245 - 249
Autores: Català-Moll, F.; Ferreté-Bonastre, A. G.; Li, T. L.; et al.

Título: Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Revista: NUCLEIC ACIDS RESEARCH

ISSN: 0305-1048 Vol.49 N° 9 2021 págs. 5057 - 5073

Resumen

Activation-induced deaminase (AID) initiates antibody diversification in germinal center B cells by deaminating cytosines, leading to somatic hypermutation and class-switch recombination. Loss-of-function mutations in AID lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated deamination has been proposed as leading to active demethylation of 5-methycytosines in the DNA, although evidence both supports and casts doubt on such a role. In this study, using whole-genome bisulfite sequencing of HIGM2 B cells, we investigated direct AID involvement in active DNA demethylation. HIGM2 naive and memory B cells both display widespread DNA methylation alterations, of which similar to 25% are attributable to active DNA demethylation. For genes that undergo active demethylation that is impaired in HIGM2 individuals, our analysis indicates that AID is not directly involved. We demonstrate that the widespread alterations in the DNA methylation and expression profiles of HIGM2 naive B cells result from premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data support a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.
Autores: Haertle, L.; Barrio, S.; Munawar, U.; et al.

Título: Cereblon enhancer methylation and IMiD resistance in multiple myeloma

Revista: BLOOD

ISSN: 0006-4971 Vol.138 N° 18 2021 págs. 1721 - 1726

Resumen

Cereblon is the direct binding target of the immunomodulatory drugs (IMiDs) that are commonly used to treat multiple myeloma (MM), the second most frequent hematologic malignancy. Patients respond well to initial treatment with IMiDs, but virtually all patients develop drug resistance over time, and the underlying mechanisms are poorly understood. We identified an as yet undescribed DNA hypermethylation in an active intronic CRBN enhancer. Differential hypermethylation in this region was found to be increased in healthy plasma cells, but was more pronounced in IMiD-refractory MM. Methylation significantly correlated with decreased CRBN expression levels. DNA methyltransferase inhibitor (DNTMi) in vitro experiments induced CRBN enhancer demethylation, and sensitizing effects on lenalidomide treatment were observed in 2 MM cell lines. Thus, we provide first evidence that aberrant CRBN DNA methylation is a novel mechanism of IMiD resistance in MM and may predict IMiD response prior to treatment.
Autores: Vilarrasa-Blasi, R.; Soler-Vila, P.; Verdaguer-Dot, N.; et al.

Título: Dynamics of genome architecture and chromatin function during human B cell differentiation and neoplastic transformation

Revista: NATURE COMMUNICATIONS

ISSN: 2041-1723 Vol.12 N° 1 2021

Resumen

To investigate the three-dimensional (3D) genome architecture across normal B cell differentiation and in neoplastic cells from different subtypes of chronic lymphocytic leukemia and mantle cell lymphoma patients, here we integrate in situ Hi-C and nine additional omics layers. Beyond conventional active (A) and inactive (B) compartments, we uncover a highly-dynamic intermediate compartment enriched in poised and polycomb-repressed chromatin. During B cell development, 28% of the compartments change, mostly involving a widespread chromatin activation from naive to germinal center B cells and a reversal to the naive state upon further maturation into memory B cells. B cell neoplasms are characterized by both entity and subtype-specific alterations in 3D genome organization, including large chromatin blocks spanning key disease-specific genes. This study indicates that 3D genome interactions are extensively modulated during normal B cell differentiation and that the genome of B cell neoplasias acquires a tumor-specific 3D genome architecture.
Autores: Sargas, C.; Ayala, R.; Chillón, M. C.; et al.

Título: Networking for advanced molecular diagnosis in acute myeloid leukemia patients is possible: the PETHEMA NGS-AML project

Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL

ISSN: 0390-6078 Vol.106 N° 12 2021 págs. 3079 - 3089

Resumen

Next-Generation Sequencing has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia. However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. To overcome this challenge, the PETHEMA group established a nationwide network of reference laboratories aimed to deliver molecular results in the clinics. We report the technical cross-validation results for next-generation sequencing panel genes during the standardization process and the clinical validation in 823 samples of 751 patients with newly diagnosed or refractory/relapse acute myeloid leukemia. Two cross-validation rounds were performed in seven nationwide reference laboratories in order to reach a consensus regarding quality metrics criteria and variant reporting. In the pre-standardization cross-validation round, an overall concordance of 60.98% was obtained with a great variability in selected genes and conditions across laboratories. After consensus of relevant genes and optimization of quality parameters the overall concordance rose to 85.57% in the second cross-validation round. We show that a diagnostic network with harmonized next-generation sequencing analysis and reporting in seven experienced laboratories is feasible in the context of a scientific group.
Autores: Polverelli, N. (Autor de correspondencia); Mauff, K.; Kroger, N.; et al.

Título: Impact of spleen size and splenectomy on outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis: A retrospective analysis by the chronic malignancies working party on behalf of European society for blood and marrow transplantation (EBMT)

Revista: AMERICAN JOURNAL OF HEMATOLOGY

ISSN: 0361-8609 Vol.96 N° 1 2021 págs. 69 - 79

Resumen

The role of spleen size and splenectomy for the prediction of post-allogeneic hematopoietic stem cell transplant (allo-HCT) outcome in myelofibrosis remains under debate. In EBMT registry, we identified a cohort of 1195 myelofibrosis patients transplanted between 2000-2017 after either fludarabine-busulfan or fludarabine-melphalan regimens. Overall, splenectomy was performed in 202 (16.9%) patients and its use decreased over time (28.3% in 2000-2009 vs 14.1% in 2010-2017 period). By multivariate analysis, splenectomy was associated with less NRM (HR 0.64, 95% CI 0.44-0.93, P = .018) but increased risk of relapse (HR 1.43, 95% CI 1.01-2.02, P = .042), with no significant impact on OS (HR 0.86, 95% CI 0.67-1.12, P = .274). However, in subset analysis comparing the impact of splenectomy vs specific spleen sizes, for patients with progressive disease, an improved survival was seen in splenectomised subjects compared to those patients with a palpable spleen length >= 15 cm (HR 0.44, 95% CI 0.28-0.69, P < .001), caused by a significant reduction in NRM (HR 0.26, 95% CI 0.14-0.49, P < .001), without significantly increased relapse risk (HR 1.47, 95% CI 0.87-2.49, P = .147). Overall, despite the possible biases typical of retrospective cohorts, this study highlights the potential detrimental effect of massive splenomegaly in transplant outcome and supports the role of splenectomy for myelofibrosis patients with progressive disease and large splenomegaly.
Autores: Grigorian-Shamagian, L.; Sanz-Ruiz, R.; Climent, A.; et al.

Título: Insights into therapeutic products, preclinical research models, and clinical trials in cardiac regenerative and reparative medicine: where are we now and the way ahead. Current opinion paper of the ESC Working Group on Cardiovascular Regenerative and Reparative Medicine

Revista: CARDIOVASCULAR RESEARCH

ISSN: 0008-6363 Vol.117 N° 6 2021 págs. 1428 - 1433

Resumen

Great expectations have been set around the clinical potential of regenerative and reparative medicine in the treatment of cardiovascular diseases [i.e. in particular, heart failure (HF)]. Initial excitement, spurred by encouraging preclinical data, resulted in a rapid translation into clinical research. The sobering outcome of the resulting clinical trials suggests that preclinical testing may have been insufficient to predict clinical outcome. A number of barriers for clinical translation include the inherent variability of the biological products and difficulties to develop potency and quality assays, insufficient rigour of the preclinical research and reproducibility of the results, manufacturing challenges, and scientific irregularities reported in the last years. The failure to achieve clinical success led to an increased scrutiny and scepticism as to the clinical readiness of stem cells and gene therapy products among clinicians, industry stakeholders, and funding bodies. The present impasse has attracted the attention of some of the most active research groups in the field, which were then summoned to analyse the position of the field and tasked to develop a strategy, to re-visit the undoubtedly promising future of cardiovascular regenerative and reparative medicine, based on lessons learned over the past two decades. During the scientific retreat of the ESC Working Group on Cardiovascular Regenerative and Reparative Medicine (CARE) in November 2018, the most relevant and timely research aspects in regenerative and/or reparative medicine were presented and critically discussed, with the aim to lay out a strategy for the future development of the field. We report herein the main ideas and conclusions of that meeting.
Autores: Calvo Arnedo, Isabel; Sharma, S.; Paulo, J. A.; et al.

Título: The fission yeast FLCN/FNIP complex augments TORC1 repression or activation in response to amino acid (AA) availability

Revista: ISCIENCE

ISSN: 2589-0042 Vol.24 N° 11 2021 págs. 103338

Resumen

The target of Rapamycin complex1 (TORC1) senses and integrates several environmental signals, including amino acid (AA) availability, to regulate cell growth. Folliculin (FLCN) is a tumor suppressor (TS) protein in renal cell carcinoma, which paradoxically activates TORC1 in response to AA supplementation. Fewtractable systems formodeling FLCN-as a TS are available. Here, we characterize the FLCNcontaining complex in Schizosaccharomyces pombe ( called BFC) and show that BFC augments TORC1 repression and activation in response to AA starvation and supplementation, respectively. BFC co-immunoprecipitates V-ATPase, a TORC1 modulator, and regulates its activity in an AA-dependent manner. BFC genetic and proteomic networks identify the conserved peptide transmembrane transporter Ptr2 and the phosphoribosylformylglycinamidine synthase Ade3 as new AA-dependent regulators of TORC1. Overall, these data ascribe an additional repressive function to Folliculin in TORC1 regulation and reveal S. pombe as an excellent system for modeling the AA-dependent, FLCN-mediated repression of TORC1 in eukaryotes.
Autores: Perez-Amill, L.; Suñe, G.; Antoñana-Vildosola, A.; et al.

Título: Preclinical development of a humanized chimeric antigen receptor against B cell maturation antigen for multiple myeloma

Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL

ISSN: 0390-6078 Vol.106 N° 1 2021 págs. 173 - 184

Resumen

Multiple myeloma is a prevalent and incurable disease, despite the development of new and effective drugs. The recent development of chimeric antigen receptor (CAR)-T cell therapy has shown impressive results in the treatment of patients with relapsed or refractory hematological B cell malignancies. In the recent years, B-cell maturation antigen (BCMA) has appeared as a promising antigen to target using a variety of immuno-therapy treatments including CART cells, for MM patients. To this end, we generated clinical-grade murine CART cells directed against BCMA, named ARI2m cells. Having demonstrated its efficacy, and in an at-tempt to avoid the immune rejection of CART cells by the patient, the single chain variable fragment was humanized, creating ARI2h cells. ARI2h cells demonstrated comparable in vitro and in vivo efficacy to ARI2m cells, and superiority in cases of high tumor burden disease. In terms of inflammatory response, ARI2h cells showed a lower TNF¿ production and lower in vivo toxicity profile. Large-scale expansion of both ARI2m and ARI2h cells was efficiently conducted following Good Manufacturing Practice guidelines, obtaining the target CART cell dose required for treatment of multiple myeloma patients. Moreover, we demonstrate that soluble BCMA and BCMA released in vesicles impacts on CAR-BCMA activity. In sum-mary, this study sets the bases for the implementation of a clinical trial (EudraCT code: 2019-001472-11) to study the efficacy of ARI2h cell treatment for multiple myeloma patients.
Autores: Isidro, I. A. (Autor de correspondencia); Vicente, P.; Pais, D. A. M.; et al.

Título: Online monitoring of hiPSC expansion and hepatic differentiation in 3D culture by dielectric spectroscopy

Revista: BIOTECHNOLOGY AND BIOENGINEERING

ISSN: 0006-3592 Vol.118 N° 9 2021 págs. 3610 - 3617

Resumen

Hepatocyte-like cells derived from human-induced pluripotent stem cells (hiPSC-HLC) are expected to have important applications in drug screening and regenerative medicine. However, hiPSC-HLC are difficult to produce on a large-scale to obtain relevant numbers for such applications. The aim of this study was to implement a novel integrated strategy for scalable production of hiPSC-HLC and demonstrate the applicability of dielectric spectroscopy to monitor hiPSC expansion/differentiation processes. We cultured hiPSC as three-dimensional (3D) aggregates in stirred-tank bioreactors (STB) operated in perfusion with an in situ capacitance probe. Dissolved oxygen concentration and dilution rate were controlled along the process and after 5 days of cell expansion, the hepatic differentiation was integrated in sequential steps for 28 days. The hiPSC were able to grow as 3D aggregates and the expression of hepatic markers and albumin production after differentiation confirmed that hepatocyte differentiation improved when compared to 2D culture. These hiPSC-HLC exhibited functional characteristics of hepatocytes including glycogen storage and drug metabolization capacity. Our results also show a good correlation between the cell permittivity measured online and the aggregate biovolume measured by standard offline methods, demonstrating for the first time the potential of dielectric spectroscopy to monitor hiPSC expansion and differentiation in STB.
Autores: Zawislak, A. (Autor de correspondencia); Wozniak, K.; Aguirre Ena, Xabier; et al.

Título: Association of ABCA4 gene polymorphisms with cleft lip with or without cleft palate in the polish population

Revista: INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH

ISSN: 1661-7827 Vol.18 N° 21 2021 págs. 11483

Resumen

Background: Non-syndromic cleft lip with/without cleft palate (NSCL/P) is a common congenital condition with a complex aetiology reflecting multiple genetic and environmental factors. Single nucleotide polymorphisms (SNPs) in ABCA4 have been associated with NSCL/P in several studies, although there are some inconsistent results. This study aimed to evaluate whether two SNPs in ABCA4, namely rs4147811 and rs560426, are associated with NSCL/P occurrence in the Polish population. Methods: The study included 627 participants: 209 paediatric patients with NSCL/P and 418 healthy newborn controls. DNA was isolated from the saliva of NSCL/P patients and from umbilical cord blood in the controls. Genotyping of rs4147811 and rs560426 was performed using quantitative PCR. Results: The rs4147811 (AG genotype) SNP in ABCA4 was associated with a decreased risk of NSCL/P (odds ratio (OR) 0.57; 95% confidence interval (CI) 0.39-0.84; p = 0.004), whereas the rs560426 (GG genotype) SNP was associated with an increased risk of NSCL/P (OR 2.13; 95% CI 1.31-3.48; p = 0.002). Limitations: This study-based on the correlation between single genetic variants and the occurrence of different phenotypes-might have limited power in detecting relevant, complex inheritance patterns. ORs are often low to moderate when investigating the association of single genes with the risk of a complex trait. Another limitation was the small number of available NSCL/P samples. Conclusions: The results suggest that genetic variations in ABCA4 are important risk markers of NSCL/P in the Polish population. Further investigation in a larger study group is warranted.</p>
Autores: Rabal Gracia, María Obdulia; San José Enériz, Edurne; Aguirre Ena, Xabier; et al.

Título: Design and synthesis of novel epigenetic inhibitors targeting histone deacetylases, DNA methyltransferase 1, and lysine methyltransferase G9a with in vivo efficacy in multiple myeloma

Revista: JOURNAL OF MEDICINAL CHEMISTRY

ISSN: 0022-2623 Vol.64 N° 6 2021 págs. 3392 - 3426

Resumen

Concomitant inhibition of key epigenetic pathways involved in silencing tumor suppressor genes has been recognized as a promising strategy for cancer therapy. Herein, we report a first-in-class series of quinoline-based analogues that simultaneously inhibit histone deacetylases (from a low nanomolar range) and DNA methyltransferase-1 (from a mid-nanomolar range, IC50 < 200 nM). Additionally, lysine methyltransferase G9a inhibitory activity is achieved (from a low nanomolar range) by introduction of a key lysine mimic group at the 7-position of the quinoline ring. The corresponding epigenetic functional cellular responses are observed: histone-3 acetylation, DNA hypomethylation, and decreased histone-3 methylation at lysine-9. These chemical probes, multitarget epigenetic inhibitors, were validated against the multiple myeloma cell line MM1.S, demonstrating promising in vitro activity of 12a (CM-444) with GI(50) of 32 nM, an adequate therapeutic window (>1 log unit), and a suitable pharmacokinetic profile. In vivo, 12a achieved significant antitumor efficacy in a xenograft mouse model of human multiple myeloma.
Autores: Parra-Salinas, I. (Autor de correspondencia); Bermudez, A.; Lopez-Corral, L.; et al.

Título: Treatment of steroid-refractory chronic graft-versus-host disease with imatinib: real-life experience of the Spanish group of hematopoietic transplantation (GETH)

Revista: CLINICAL TRANSPLANTATION

ISSN: 0902-0063 Vol.35 N° 5 2021 págs. e14255

Resumen

Treatment of steroid-refractory chronic graft-versus-host disease (cGVHD) is a challenge. Here, we describe a retrospective analysis of 66 patients with steroid-refractory cGVHD treated with imatinib (starting dose of 100 mg in 70% of patients; maximum dose of 100-200 mg in 74%). Most patients had multi-organ involvement (>= 2 organs, 83%), with the most affected being skin (85%), oral mucosa (55%), eyes (42%), and lungs (33%). The overall response rate was 41% (21 partial and three complete responses). The organ with the best response rate was the skin (46%), followed by gastrointestinal tract (43%), liver (41%), the oral mucosa (36%), eyes (29%), and lungs (18%). Imatinib led to steroid tapering in 17/38 patients. Twenty-five (38%) patients experienced imatinib-related adverse events, comprising extra-hematologic toxicity (n = 24, 36%) and hematologic toxicity (n = 6, 9%). No cases of grade 4-5 toxicity were reported. The main causes of imatinib discontinuation were treatment failure (52%) and toxicity (9%). After a median follow-up of 41 months, the 3-year overall survival was 81%, with no difference between imatinib responders and non-responders. These real-life results show that imatinib is safe and has moderate efficacy in patients with heavily pre-treated cutaneous sclerotic cGVHD; however, activity against lung cGVHD is very limited.
Autores: Garcia-Gomez, A. (Autor de correspondencia); Li, T.; de la Calle-Fabregat, C.; et al.

Título: Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease

Revista: NATURE COMMUNICATIONS

ISSN: 2041-1723 Vol.12 N° 1 2021 págs. 421

Resumen

Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on bone marrow mesenchymal stromal cells (MSCs). MM-MSCs exhibit abnormal transcriptomes, suggesting the involvement of epigenetic mechanisms governing their tumor-promoting functions and prolonged osteoblast suppression. Here, we identify widespread DNA methylation alterations of bone marrow-isolated MSCs from distinct MM stages, particularly in Homeobox genes involved in osteogenic differentiation that associate with their aberrant expression. Moreover, these DNA methylation changes are recapitulated in vitro by exposing MSCs from healthy individuals to MM cells. Pharmacological targeting of DNMTs and G9a with dual inhibitor CM-272 reverts the expression of hypermethylated osteogenic regulators and promotes osteoblast differentiation of myeloma MSCs. Most importantly, CM-272 treatment prevents tumor-associated bone loss and reduces tumor burden in a murine myeloma model. Our results demonstrate that epigenetic aberrancies mediate the impairment of bone formation in MM, and its targeting by CM-272 is able to reverse MBD. Mesenchymal stromal cells (MSCs) have been shown to support multiple myeloma (MM) development. Here, MSCs isolated from the bone marrow of MM patients are shown to have altered DNA methylation patterns and a methyltransferase inhibitor reverts MM-associated bone loss and reduces tumour burden in MM murine models.
Autores: Jagannath, S. (Autor de correspondencia); Lin, Y.; Goldschmidt, H.; et al.

Título: KarMMa-RW: comparison of idecabtagene vicleucel with real-world outcomes in relapsed and refractory multiple myeloma

Revista: BLOOD CANCER JOURNAL

ISSN: 2044-5385 Vol.11 N° 6 2021 págs. 116

Resumen

Patients with relapsed and refractory multiple myeloma (RRMM) who are triple-class exposed (to an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody) have limited treatment options and there is no standard of care. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T-cell therapy, demonstrated efficacy in triple-class exposed RRMM patients in the KarMMa trial (NCT03361748). In this retrospective study (KarMMa-RW), patient-level data from triple-class exposed RRMM patients were merged into a single data model and compared with KarMMa using trimmed stabilized inverse probability of treatment weighting. Endpoints included overall response rate (ORR; primary), rate of very good partial response or better (>= VGPR), progression-free survival (PFS), and overall survival (OS). Of 1949 real-world triple-class exposed RRMM patients, 190 received subsequent (index) line of therapy and met KarMMa eligibility criteria (Eligible RRMM cohort). With a median follow-up of 13.3 months in KarMMa and 10.2 months in Eligible RRMM, ORR, and >= VGPR were significantly improved in KarMMa versus Eligible RRMM (ORR, 76.4% vs 32.2%; >= VGPR, 57.9% vs 13.7%; both P < 0.0001) as were PFS (11.6 vs 3.5 months; P = 0.0004) and OS (20.2 vs 14.7 months; P = 0.0006). This study demonstrated that ide-cel significantly improved responses and survival compared with currently available therapies in triple-class exposed RRMM.
Autores: Valcárcel, L. V.; Amundarain, A.; Kulis, M.; et al.

Título: Gene expression derived from alternative promoters improves prognostic stratification in multiple myeloma

Revista: LEUKEMIA

ISSN: 0887-6924 Vol.35 N° 10 2021 págs. 3012 - 3016

Resumen

Clinical and genetic risk factors are currently used in multiple myeloma (MM) to stratify patients and to design specific therapies. However, these systems do not capture the heterogeneity of the disease supporting the development of new prognostic factors. In this study, we identified active promoters and alternative active promoters in 6 different B cell subpopulations, including bone-marrow plasma cells, and 32 MM patient samples, using RNA-seq data. We find that expression initiated at both regular and alternative promoters was specific of each B cell subpopulation or MM plasma cells, showing a remarkable level of consistency with chromatin-based promoter definition. Interestingly, using 595 MM patient samples from the CoMMpass dataset, we observed that the expression derived from some alternative promoters was associated with lower progression-free and overall survival in MM patients independently of genetic alterations. Altogether, our results define cancer-specific alternative active promoters as new transcriptomic features that can provide a new avenue for prognostic stratification possibilities in patients with MM.
Autores: Dhillon, P.; Park, J. (Autor de correspondencia); del-Pozo, C. H.; et al.

Título: The nuclear receptor ESRRA protects from kidney disease by coupling metabolism and differentiation

Revista: CELL METABOLISM

ISSN: 1550-4131 Vol.33 N° 2 2021 págs. 379 - 394.e8

Resumen

Kidney disease is poorly understood because of the organ's cellular diversity. We used single-cell RNA sequencing not only in resolving differences in injured kidney tissue cellular composition but also in cell type-specific gene expression in mouse models of kidney disease. This analysis highlighted major changes in cellular diversity in kidney disease, which markedly impacted whole-kidney transcriptomics outputs. Cell type-specific differential expression analysis identified proximal tubule (PT) cells as the key vulnerable cell type. Through unbiased cell trajectory analyses, we show that PT cell differentiation is altered in kidney disease. Metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and most reproducible association with PT cell differentiation and disease. Coupling of cell differentiation and the metabolism was established by nuclear receptors (estrogen-related receptor alpha [ESRRA] and peroxisomal proliferation-activated receptor alpha [PPARA]) that directly control metabolic and PT-cell-specific gene expression in mice and patient samples while protecting from kidney disease in the mouse model.
Autores: Steensma, D. P.; Wermke, M.; Klimek, V. M.; et al.

Título: Phase I first-in-human dose escalation study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms

Revista: LEUKEMIA

ISSN: 0887-6924 Vol.35 N° 12 2021 págs. 3542 - 3550

Resumen

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1-40 mg, n = 65) and schedule II (21 days on/7 days off, 7-20 mg, n = 19); 27 patients received treatment for >= 180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.
Autores: Carrasco Leon, Arantxa; Ezponda Itoiz, Teresa; Meydan, C.; et al.

Título: Characterization of complete lncRNAs transcriptome reveals the functional and clinical impact of lncRNAs in multiple myeloma

Revista: LEUKEMIA

ISSN: 0887-6924 Vol.35 N° 5 2021 págs. 1438 - 1450

Resumen

Multiple myeloma (MM) is an incurable disease, whose clinical heterogeneity makes its management challenging, highlighting the need for biological features to guide improved therapies. Deregulation of specific long non-coding RNAs (lncRNAs) has been shown in MM, nevertheless, the complete lncRNA transcriptome has not yet been elucidated. In this work, we identified 40,511 novel lncRNAs in MM samples. lncRNAs accounted for 82% of the MM transcriptome and were more heterogeneously expressed than coding genes. A total of 10,351 overexpressed and 9,535 downregulated lncRNAs were identified in MM patients when compared with normal bone-marrow plasma cells. Transcriptional dynamics study of lncRNAs in the context of normal B-cell maturation revealed 989 lncRNAs with exclusive expression in MM, among which 89 showed de novo epigenomic activation. Knockdown studies on one of these lncRNAs, SMILO (specific myeloma intergenic long non-coding RNA), resulted in reduced proliferation and induction of apoptosis of MM cells, and activation of the interferon pathway. We also showed that the expression of lncRNAs, together with clinical and genetic risk alterations, stratified MM patients into several progression-free survival and overall survival groups. In summary, our global analysis of the lncRNAs transcriptome reveals the presence of specific lncRNAs associated with the biological and clinical behavior of the disease.
Autores: Cordero, O. J. (Autor de correspondencia); Rafael-Vidal, C.; Varela-Calvino, R.; et al.

Título: Distinctive CD26 expression on CD4 T-cell subsets

Revista: BIOMOLECULES

ISSN: 2218-273X Vol.11 N° 10 2021 págs. 1446

Resumen

Immune system CD4 T-cells with high cell-surface CD26 expression show anti-tumoral properties. When engineered with a chimeric antigen receptor (CAR), they incite strong responses against solid cancers. This subset was originally associated to human CD4 T helper cells bearing the CD45R0 effector/memory phenotype and later to Th17 cells. CD26 is also found in soluble form (sCD26) in several biological fluids, and its serum levels correlate with specific T cell subsets. However, the relationship between glycoprotein sCD26 and its dipeptidyl peptidase 4 (DPP4) enzymatic activity, and cell-surface CD26 expression is not well understood. We have studied ex vivo cell-surface CD26 and in vitro surface and intracellular CD26 expression and secretome's sCD26 in cultured CD4 T cells under different polarization conditions. We show that most human CD26negative CD4 T cells in circulating lymphocytes are central memory (T-CM) cells while CD26high expression is present in effector Th1, Th2, Th17, and T-EM (effector memory) cells. However, there are significant percentages of Th1, Th2, Th17, and Th22 CD26 negative cells. This information may help to refine the research on CAR-Ts. The cell surface CD45R0 and CD26 levels in the different T helper subsets after in vitro polarization resemble those found ex vivo. In the secretomes of these cultures there was a significant amount of sCD26. However, in all polarizations, including Th1, the levels of sCD26 were lower (although not significantly) compared to the Th0 condition (activation without polarization). These differences could have an impact on the various physiological functions proposed for sCD26/DPP4.</p>
Autores: Campo Ezquibela, Aránzazu (Autor de correspondencia); González-Ruíz, J. M.; Andreu Oltra, Enrique José; et al.

Título: Endobronchial autologous bone marrow-mesenchymal stromal cells in idiopathic pulmonary fibrosis: a phase I trial

Revista: ERJ OPEN RESEARCH

ISSN: 2312-0541 Vol.7 N° 2 2021 págs. 00773 - 2020

Resumen

Rationale: Idiopathic pulmonary fibrosis (IPF) has a dismal prognosis. Mesenchymal stromal cells (MSCs) have shown benefit in other inflammatory diseases. Objectives: To evaluate the safety and feasibility of endobronchial administration of bone marrow autologous MSCs (BM-MSC) in patients with mild-to-moderate IPF. Methods: A phase I multicentre clinical trial (ClinicalTrials.gov NCT01919827) with a single endobronchial administration of autologous adult BM-MSCs in patients diagnosed with mild-to-moderate IPF. In a first escalating-dose phase, three patients were included sequentially in three dose cohorts (10×106, 50×106 and 100×106 cells). In a second phase, nine patients received the highest tolerated dose. Follow-up with pulmonary function testing, 6-min walk test and St George¿s Respiratory Questionnaire was done at 1, 2, 3, 6 and 12 months, and with computed tomography at 3, 6 and 12 months. Results: 21 bone marrow samples were obtained from 17 patients. Three patients were excluded from treatment due to chromosome aberrations detected in MSCs after culture, and one patient died before treatment. Finally, 13 patients received the BM-MSC infusion. No treatment-related severe adverse events were observed during follow-up. Compared to baseline, the mean forced vital capacity showed an initial decline of 8.1% at 3 months. The number of patients without functional progression was six (46%) at 3 months and three (23%) at 12 months. Conclusions: The endobronchial infusion of BM-MSCs did not cause immediate serious adverse events in IPF patients, but a relevant proportion of patients suffered clinical and/or functional progression. Genomic instability of BM-MSCs during culture found in three patients may be troublesome for the use of autologous MSCs in IPF patients
Autores: Antelo, M. L. (Autor de correspondencia); Altuna, A.; Gimeno, J. J.; et al.

Título: Engraftment after autologous hematopoietic stem cell transplantation in patients mobilized with Plerixafor: a retrospective, multicenter study of a large series of patients

Revista: TRANSFUSION AND APHERESIS SCIENCE

ISSN: 1473-0502 Vol.60 N° 3 2021 págs. 103130

Resumen

Plerixafor (PLX) appears to effectively enhance hematopoietic stem-cell mobilization prior to autologous hematopoietic stem cell transplantation (auto-HCT). However, the quality of engraftment following auto-HCT has been little explored. Here, engraftment following auto-HCT was assessed in patients mobilized with PLX through a retrospective, multicenter study of 285 consecutive patients. Information on early and 100-day post-transplant engraftment was gathered from the 245 patients that underwent auto-HCT. The median number of PLX days to reach the stem cell collection goal (>= 2 x 10(6) CD34(+) cells/kg) was 1 (range 1-4) and the median PLX administration time before apheresis was 11 h (range 1-18). The median number of apheresis sessions to achieve the collection goal was 2 (range 1-5) and the mean number of CD34(+) cells collected was 2.95 x 10(6)/kg (range 0-30.5). PLX administration was safe, with only 2 mild and transient gastrointestinal adverse events reported. The median time to achieve an absolute neutrophil count (ANC) >500/mu L was 11 days (range 3-31) and the median time to platelet recovery >20 x 10(3)/mu L was 13 days (range 5-69). At 100 days after auto-HCT, the platelet count was 137 x 10(9)/L (range 7-340), the ANC was 2.3 x 10(9)/L (range 0.1-13.0), and the hemoglobin concentration was 123 g/L (range 79-165). PLX use allowed auto-HCT to be performed in a high percentage of poorly mobilized patients, resulting in optimal medium-term engraftment in the majority of patients in whom mobilization failed, in this case mainly due to suboptimal peripheral blood CD34(+) cell concentration on day +4 or low CD34(+) cell yield on apheresis.
Autores: Chari, A. (Autor de correspondencia); Rodríguez Otero, Paula; McCarthy, H. ; et al.

Título: Subcutaneous daratumumab plus standard treatment regimens in patients with multiple myeloma across lines of therapy (PLEIADES): an open-label Phase II study

Revista: BRITISH JOURNAL OF HAEMATOLOGY

ISSN: 0007-1048 Vol.192 N° 5 2021 págs. 869 - 878

Resumen

Daratumumab is a CD38-targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of daratumumab (DARA SC) in combination with standard-of-care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D-VRd) for transplant-eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/prednisone (D-VMP) for transplant-ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D-Rd) for relapsed/refractory MM. In total, 199 patients were treated (D-VRd,n = 67; D-VMP,n = 67; D-Rd,n = 65). The primary endpoints were met for all cohorts: the >= very good partial response (VGPR) rate after four 21-day induction cycles for D-VRd was 71 center dot 6% [90% confidence interval (CI) 61 center dot 2-80 center dot 6%], and the overall response rates (ORRs) for D-VMP and D-Rd were 88 center dot 1% (90% CI 79 center dot 5-93 center dot 9%) and 90 center dot 8% (90% CI 82 center dot 6-95 center dot 9%). With longer median follow-up for D-VMP and D-Rd (14 center dot 3 and 14 center dot 7 months respectively), responses deepened (ORR: 89 center dot 6%, 93 center dot 8%; >= VGPR: 77 center dot 6%, 78 center dot 5%), and minimal residual disease-negativity (10(-5)) rates were 16 center dot 4% and 15 center dot 4%. Infusion-related reactions across all cohorts were infrequent (<= 9 center dot 0%) and mild. The median DARA SC administration time was 5 min. DARA SC with standard-of-care regimens demonstrated comparable clinical activity to DARA IV-containing regimens, with low infusion-related reaction rates and reduced administration time.
Autores: Bailén-Almorox, R.; Pascual-Cascón, M. J.; Guerreiro, M.; et al.

Título: Resultados del trasplante alogénico HLA idéntico con ciclofosfamida post-trasplante versus trasplante haploidéntico en pacientes con Leucemia Mieloide Aguda: experiencia del Grupo Español De Trasplante Hematopoyético (GETH)

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 2021 págs. 37 - 38
Autores: Raje, N. S.; Berdeja, J. G.; Rodríguez Otero, Paula; et al.

Título: KarMMa-7, a phase 1/2, dose-finding and dose-expansion study of combination therapies with idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR t cell therapy for relapsed/refractory multiple myeloma (RRMM)

Revista: BLOOD

ISSN: 0006-4971 Vol.138 N° Supl. 1 2021
Autores: Wong, L.; Lamba, M.; Núñez, M. D. J.; et al.

Título: A Phase 1 study Of CC-92480, a novel CELMoD agent, in patients with relapsed/refractory multiple myeloma: pharmacodynamic effects of dose and schedule

Revista: BRITISH JOURNAL OF HAEMATOLOGY

ISSN: 0007-1048 Vol.193 N° Supl. 1 2021 págs. 152 - 153
Autores: Villar Fernández, Sara; Ariceta, B.; Agirre, X.; et al.

Título: Caracterización transcripcional de la leucemia mieloide aguda al diagnóstico en el paciente mayor con identificación de nuevos grupos pronósticos

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 86 - 87
Autores: Oriol, A.; Manier, S.; Kansagra, A.; et al.

Título: Características de la neurotoxicidad asociada a Idecabtagene Vicleucel (IDE-CEL, BB2121) en pacientes con mieloma múltiple en recaída y refractario del estudio pivotal fase 2 KARMMA

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 78 - 79
Autores: Viñado, A. C.; Calvo Arnedo, Isabel; Cenzano Armendariz, Itziar; et al.

Título: El microambiente de la médula ósea regula el metabolismo oxidativo de las células madre de la Leucemia Mieloide Aguda

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 82 - 82
Autores: Viñado, A. C.; Calvo Arnedo, Isabel; Cenzano Armendariz, Itziar (Autor de correspondencia); et al.

Título: Nuevos regímenes de acondicionamiento no-genotóxico para el trasplante de progenitores hematopoyéticos en inmunodeficiencias primarias: AT como prueba de concepto

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 42 - 43
Autores: Berastegui Zufiaurre, Nerea; Ainciburu Fernandez, Marina; Alfonso Piérola, Ana; et al.

Título: Caracterización de alteraciones transcripcionales en pacientes con síndrome mielodisplásico con deleción 5Q

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 99 - 100
Autores: Molero Yordi, A.; Tazon, B.; Gallur, L.; et al.

Título: Microenvironment profiling in myelodysplastic syndromes and its relationship to clonal hematopoiesis and disease progression

Revista: BLOOD

ISSN: 0006-4971 Vol.138 N° Supl. 1 2021
Autores: López Cadenas, F.; Badiella Busquets, L.; Bernal Castillo, T.; et al.

Título: Características clínico-biológicas y pronósticas de los SMD de bajo riesgo sin sideroblastos en anillo y comparativa con su contrapartida con sideroblastos en anillo

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 244 - 245
Autores: Jiménez Solas, T.; Muntion Olave, S.; López, F.; et al.

Título: Mesenchymal stromal cells may enhance residual healthy haematopoiesis in low-risk MDS patients

Revista: LEUKEMIA RESEARCH

ISSN: 0145-2126 Vol.108 2021 págs. S39 - S39
Autores: Molero, A.; Gallur, L.; Tazón-Vega, B.; et al.

Título: Phenotype and genotype of natural killers in myelodisplasitic syndrome

Revista: LEUKEMIA RESEARCH

ISSN: 0145-2126 Vol.108 2021 págs. S35 - S36
Autores: Calviño Sampedro, Cristina; Ceballos, C.; Inoges Sancho, Susana Inmaculada; et al.

Título: Evaluación funcional de células CAR-T ANTI-CD33 generadas a partir de donantes sanos y pacientes con leucemia mieloide aguda

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 59 - 59
Autores: Molero, A.; Tazón-Vega, B.; Gallur, L.; et al.

Título: Relación entre las poblaciones de células inmunitarias y el estado mutacional en los síndromes mielodisplásicos

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 240 - 241
Autores: Calvo Arnedo, Isabel; Cenzano Armendariz, Itziar; Ye, J.; et al.

Título: Descripción de la complejidad celular del microambiente de la médula ósea humana mediante tecnología ómica y biología de sistemas

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 119 - 120
Autores: Parra Salinas, I. M.; Bermúdez Rodríguez, A.; López Corral, L.; et al.

Título: Tratamiento con imatinib de la Enfermedad de Injerto contra Receptor Crónica refractaria a corticosteroides: experiencia del Grupo Español de Trasplante Hematopoyético y Terapia Celular (GETH)

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 275 - 276
Autores: Molero, A.; Tazón-Vega, B.; Gallur, L.; et al.

Título: Relation between inmune cell populations and malignant clone mutational status in myelodysplastic syndromes

Revista: LEUKEMIA RESEARCH

ISSN: 0145-2126 Vol.108 2021 págs. S34 - S35
Autores: Ainciburu Fernandez, Marina; Ezponda Itoiz, Teresa; Berastegui Zufiaurre, Nerea; et al.

Título: El análisis computacional de la hematopoyesis mediante single cell RNASEQ revela alteraciones asociadas con envejecimiento y patología mieloide

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 119 - 119
Autores: Martin Mallo, Angel; Palacios Berraquero, María Luisa; San Martín Úriz, Patxi; et al.

Título: Efecto del estadío de la enfermedad sobre el fenotipo y funcionalidad de células CAR-T en pacientes con MM

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 70 - 70
Autores: Palacios Berraquero, María Luisa; Berastegui Zufiaurre, Nerea; Burgos Rodríguez, Leire; et al.

Título: Efecto paracrino de las citoquinas secretadas por células CAR-T como posible mecanismo etiopatogénico de las citopenias asociadas a estos tratamientos

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 260 - 260
Autores: Gimenez Camino, Naroa; San José Enériz, Edurne; Miranda, E.; et al.

Título: Efecto sinérgico de nuevos inhibidores HDACS con fármacos quimioterápicos en la Leucemia Mieloide Aguda

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 89 - 90
Autores: Rodríguez Márquez, Paula; Calleja Cervantes, María Erendira; SERRANO SANZ, Guillermo; et al.

Título: Papel de los niveles de expresión del car en la eficacia antitumoral de las células CAR-T

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 58 - 59
Autores: Molero, A.; Gallur, L.; Tatón-Vega, B.; et al.

Título: Fenotipo y genotipo de las natural killers en el síndrome mielodisplásico

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 241 - 242
Autores: Vítores Valcárcel, L.; Amundarain, A. ; Kulis, M.; et al.

Título: La expresión génica derivada de promotores alternativos mejora la estratificación del pronóstico en el mieloma múltiple

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 68 - 69
Autores: Barrena Acuña, N.; Vitores Valcárcel, L.; Olaverri Mendizabal, L.; et al.

Título: Identificación de las alteraciones del transcriptoma metabólico en el mieloma múltiple

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 68 - 68
Autores: Tamariz Amador, Luis Esteban; Rodríguez Otero, Paula; Jiménez de Ubieto, A.; et al.

Título: Valor pronóstico de la cinética de la respuesta sérica en pacientes con mieloma múltiple de nuevo diagnóstico

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.106 N° 10 s2 2021 págs. 64 - 65
Autores: Galluzzi, L. (Autor de correspondencia); Vitale, I.; Warren, S.; et al.

Título: Consensus guidelines for the definition, detection and interpretation of immunogenic cell death

Revista: JOURNAL FOR IMMUNOTHERAPY OF CANCER

ISSN: 2051-1426 Vol.8 N° 1 2020 págs. e000337

Resumen

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
Autores: Sánchez-Guijo, F. ; García-Olmo, D.; Prosper Cardoso, Felipe; et al.

Título: Spanish Cell Therapy Network (TerCel): 15 years of successful collaborative translational research

Revista: CYTOTHERAPY

ISSN: 1465-3249 Vol.22 N° 1 2020 págs. 1 - 5

Resumen

In the current article we summarize the 15-year experience of the Spanish Cell Therapy Network (TerCel), a successful collaborative public initiative funded by the Spanish government for the support of nationwide translational research in this important area. Thirty-two research groups organized in three programs devoted to cardiovascular, neurodegenerative and immune-inflammatory diseases, respectively, currently form the network. Each program has three working packages focused on basic science, pre-clinical studies and clinical application. TerCel has contributed during this period to boost the translational research in cell therapy in Spain, setting up a network of Good Manufacturing Practice-certified cell manufacturing facilities- and increasing the number of translational research projects, publications, patents and clinical trials of the participating groups, especially those in collaboration. TerCel pays particular attention to the public-private collaboration, which, for instance, has led to the development of the first allogeneic cell therapy product approved by the European Medicines Agency, Darvadstrocel. The current collaborative work is focused on the development of multicenter phase 2 and 3 trials that could translate these therapies to clinical practice for the benefit of patients.
Autores: Rodríguez Otero, Paula; Reis de Carvalho, Joana Sofía; Alfonso Piérola, Ana; et al.

Título: Single-institution experience in clinical trials during the COVID-19 pandemic in Spain: not so bad after all?

Revista: JCO GLOBAL ONCOLOGY

ISSN: 2687-8941 Vol.6 2020 págs. 904 - 905
Autores: Soria-Juan, B.; Escacena, N. ; Capilla-Gonzalez, V.; et al.

Título: Cost-Effective, Safe, and Personalized Cell Therapy for Critical Limb Ischemia in Type 2 Diabetes Mellitus (vol 10, 1151, 2019)

Revista: FRONTIERS IN IMMUNOLOGY

ISSN: 1664-3224 Vol.11 2020
Autores: Palomo, L.; Ibáñez, M.; Abáigar, M.; et al.

Título: Spanish Guidelines for the use of targeted deep sequencing in myelodysplastic syndromes and chronic myelomonocytic leukaemia

Revista: BRITISH JOURNAL OF HAEMATOLOGY

ISSN: 0007-1048 2020

Resumen

The landscape of medical sequencing has rapidly changed with the evolution of next generation sequencing (NGS). These technologies have contributed to the molecular characterization of the myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), through the identification of recurrent gene mutations, which are present in >80% of patients. These mutations contribute to a better classification and risk stratification of the patients. Currently, clinical laboratories include NGS genomic analyses in their routine clinical practice, in an effort to personalize the diagnosis, prognosis and treatment of MDS and CMML. NGS technologies have reduced the cost of large-scale sequencing, but there are additional challenges involving the clinical validation of these technologies, as continuous advances are constantly being made. In this context, it is of major importance to standardize the generation, analysis, clinical interpretation and reporting of NGS data. To that end, the Spanish MDS Group (GESMD) has expanded the present set of guidelines, aiming to establish common quality standards for the adequate implementation of NGS and clinical interpretation of the results, hoping that this effort will ultimately contribute to the benefit of patients with myeloid malignancies.
Autores: Sanchez-Guijo, F.; Garcia-Arranz, M.; Lopez-Parra, M.; et al.

Título: Adipose-derived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation. A proof of concept study

Revista: ECLINICALMEDICINE

ISSN: 2589-5370 Vol.25 2020 págs. 100454

Resumen

Background: Identification of effective treatments in severe cases of COVID-19 requiring mechanical ventilation represents an unmet medical need. Our aim was to determine whether the administration of adipose-tissue derived mesenchymal stromal cells (AT-MSC) is safe and potentially useful in these patients. Methods: Thirteen COVID-19 adult patients under invasive mechanical ventilation who had received previous antiviral and/or anti-inflammatory treatments (including steroids, lopinavir/ritonavir, hydroxychloroquine and/or tocilizumab, among others) were treated with allogeneic AT-MSC. Ten patients received two doses, with the second dose administered a median of 3 days (interquartile range-IQR- 1 day) after the first one. Two patients received a single dose and another patient received 3 doses. Median number of cells per dose was 0.98 × 106 (IQR 0.50 × 106) AT-MSC/kg of recipient's body weight. Potential adverse effects related to cell infusion and clinical outcome were assessed. Additional parameters analyzed included changes in imaging, analytical and inflammatory parameters. Findings: First dose of AT-MSC was administered at a median of 7 days (IQR 12 days) after mechanical ventilation. No adverse events were related to cell therapy. With a median follow-up of 16 days (IQR 9 days) after the first dose, clinical improvement was observed in nine patients (70%). Seven patients were extubated and discharged from ICU while four patients remained intubated (two with an improvement in their ventilatory and radiological parameters and two in stable condition). Two patients died (one due to massive gastrointestinal bleeding unrelated to MSC therapy). Treatment with AT-MSC was followed by a decrease in inflammatory parameters (reduction in C-reactive protein, IL-6, ferritin, LDH and d-dimer) as well as an increase in lymphocytes, particularly in those patients with clinical improvement. Interpretation: Treatment with intravenous administration of AT-MSC in 13 severe COVID-19 pneumonia under mechanical ventilation in a small case series did not induce significant adverse events and was followed by clinical and biological improvement in most subjects.
Autores: Aguilera-Diaz, A.; Larráyoz Ilundáin, María José; Palomino-Echeverria, S.; et al.

Título: Strategy for identification of a potential inherited leukemia predisposition in a 299 patient's cohort with tumor-only sequencing data

Revista: LEUKEMIA RESEARCH

ISSN: 0145-2126 Vol.95 2020

Resumen

Myeloid neoplasms (MN) are usually sporadic late-onset cancers; nevertheless, growing evidence suggests that similar to 5% of the cases could emerge as a consequence of inherited predisposition. Distinguishing somatic from germline variants is of vital importance, in order to establish an appropriate individualized management and counsel the patients and their relatives. Since many of the genes associated with myeloid neoplasm germline predisposition (MNGP) are also affected in sporadic MN, we intended to design a strategy to identify potentially inherited variants in a tumor only NGS panel in a cohort of 299 patients with a variety of MN. We considered as indicative of potential inherited origin, variants detected in BM sample at a similar to 50% VAF classified as pathogenic, likely pathogenic or of unknown significance detected in MNGP-related genes. A total of 104 suspicious variants from 90 patients were filtered-in in tumor samples. Mutational patterns, follow-up data, and sequencing of a range of non-myeloid tissues were used for narrowing down the list of suspicious variants, and ultimately discriminate their nature. Our data supports the importance of considering variants found upon tumor-only sequencing as potentially of germline origin, and we offer a pipeline to define the nature of the variants.
Autores: Yusuf, R. Z.; Sáez Ochoa, Borja; Sharda, A.; et al.

Título: Aldehyde dehydrogenase 3a2 protects AML cells from oxidative death and the synthetic lethality of ferroptosis inducers

Revista: BLOOD

ISSN: 0006-4971 Vol.136 N° 11 2020 págs. 1303 - 1316

Resumen

Metabolic alterations in cancer represent convergent effects of oncogenic mutations. We hypothesized that a metabolism-restricted genetic screen, comparing normal primary mouse hematopoietic cells and their malignant counterparts in an ex vivo system mimicking the bone marrow microenvironment, would define distinctive vulnerabilities in acute myeloid leukemia (AML). Leukemic cells, but not their normal myeloid counterparts, depended on the aldehyde dehydrogenase 3a2 (Aldh3a2) enzyme that oxidizes long-chain aliphatic aldehydes to prevent cellular oxidative damage. Aldehydes are by-products of increased oxidative phosphorylation and nucleotide synthesis in cancer and are generated from lipid peroxides underlying the non-caspase-dependent form of cell death, ferroptosis. Leukemic cell dependence on Aldh3a2 was seen across multiple mouse and human myeloid leukemias. Aldh3a2 inhibition was synthetically lethal with glutathione peroxidase-4 (GPX4) inhibition; GPX4 inhibition is a known trigger of ferroptosis that by itself minimally affects AML cells. Inhibiting Aldh3a2 provides a therapeutic opportunity and a unique synthetic lethality to exploit the distinctive metabolic state of malignant cells.
Autores: Heilig, C. E.; Badoglio, M.; Labopin, M.; et al.

Título: Haematopoietic stem cell transplantation in adult soft-tissue sarcoma: an analysis from the European Society for Blood and Marrow Transplantation

Revista: ESMO OPEN

ISSN: 2059-7029 Vol.5 N° 5 2020 págs. e000860

Resumen

Background The role of high-dose chemotherapy with autologous stem cell transplantation (ASCT) in the treatment of soft-tissue sarcoma (STS) remains an unsettled issue. Prospective clinical trials failed to prove a benefit of the procedure but were limited by small and heterogeneous patient cohorts. Thus, it is unknown if ASCT may be a valuable treatment option in specific patient subgroups. Methods The purpose of this study was to investigate the value of ASCT according to histological subtype in STS patients who were registered in the European Society for Blood and Marrow Transplantation database between 1996 and 2016. Results Median progression-free (PFS) and overall survival (OS) in the entire cohort of 338 patients were 8.3 and 19.8 months, respectively, and PFS and OS at 5 years were 13% and 25%, respectively. Analysis of outcomes in different subgroups showed that younger age, better remission status before transplantation and melphalan-based preparative regimen were predictive of benefit from ASCT, whereas histology and grading had no statistically significant impact. Conclusions Outcomes after ASCT compared favorably to those of recent trials on conventional chemotherapies and targeted therapies in STS, including histology-tailored approaches. ASCT, thus, should be reinvestigated in clinical trials focusing on defined patient subgroups.
Autores: Saenz-Pipaon, G.; San Martín Úriz, Patxi; Planell, N.; et al.

Título: Functional and transcriptomic analysis of extracellular vesicles identifies calprotectin as a new prognostic marker in peripheral arterial disease (PAD)

Revista: JOURNAL OF EXTRACELLULAR VESICLES

ISSN: 2001-3078 Vol.9 N° 1 2020 págs. 1729646

Resumen

Peripheral arterial disease (PAD) is associated with a high risk of cardiovascular events and death and is postulated to be a critical socioeconomic cost in the future. Extracellular vesicles (EVs) have emerged as potential candidates for new biomarker discovery related to their protein and nucleic acid cargo. In search of new prognostic and therapeutic targets in PAD, we determined the prothrombotic activity, the cellular origin and the transcriptomic profile of circulating EVs. This prospective study included control and PAD patients. Coagulation time (Procoag-PPL kit), EVs cellular origin and phosphatidylserine exposure were determined by flow cytometry in platelet-free plasma (n = 45 PAD). Transcriptomic profiles of medium/large EVs were generated using the MARS-Seq RNA-Seq protocol (n = 12/group). The serum concentration of the differentially expressed gene S100A9, in serum calprotectin (S100A8/A9), was validated by ELISA in control (n = 100) and PAD patients (n = 317). S100A9 was also determined in EVs and tissues of human atherosclerotic plaques (n = 3). Circulating EVs of PAD patients were mainly of platelet origin, predominantly Annexin V positive and were associated with the procoagulant activity of platelet-free plasma. Transcriptomic analysis of EVs identified 15 differentially expressed genes. Among them, serum calprotectin was elevated in PAD patients (p < 0.05) and associated with increased amputation risk before and after covariate adjustment (mean follow-up 3.6 years, p < 0.01). The combination of calprotectin with hs-CRP in the multivariate analysis further improved risk stratification (p < 0.01). Furthermore, S100A9 was also expressed in femoral plaque derived EVs and tissues. In summary, we found that PAD patients release EVs, mainly of platelet origin, highly positive for AnnexinV and rich in transcripts related to platelet biology and immune responses. Amputation risk prediction improved with calprotectin and was significantly higher when combined with hs-CRP. Our results suggest that EVs can be a promising component of liquid biopsy to identify the molecular signature of PAD patients.
Autores: Chatonnet, F. ; Pignarre, A.; Serandour, A. A.; et al.

Título: The hydroxymethylome of multiple myeloma identifies FAM72D as a 1q21 marker linked to proliferation

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.105 N° 3 2020 págs. 774 - 783

Resumen

Cell identity relies on the cross-talk between genetics and epigenetics and their impact on gene expression. Oxidation of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) is the first step of an active DNA demethylation process occurring mainly at enhancers and gene bodies and, as such, participates in processes governing cell identity in normal and pathological conditions. Although genetic alterations are well documented in multiple myeloma (MM), epigenetic alterations associated with this disease have not yet been thoroughly analyzed. To gain insight into the biology of MM, genome-wide 5hmC profiles were obtained and showed that regions enriched in this modified base overlap with MM enhancers and super enhancers and are close to highly expressed genes. Through the definition of a MM-specific 5hmC signature, we identified FAM72D as a poor prognostic gene located on 1q21, a region amplified in high risk myeloma. We further uncovered that FAM72D functions as part of the FOXM1 transcription factor network controlling cell proliferation and survival and we evidenced an increased sensitivity of cells expressing high levels of FOXM1 and FAM72 to epigenetic drugs targeting histone deacetylases and DNA methyltransferases.
Autores: Ordóñez Ciriza, Raquel; Kulis, M.; Russiñol, N.; et al.

Título: Chromatin activation as a unifying principle underlying pathogenic mechanisms in multiple myeloma

Revista: GENOME RESEARCH

ISSN: 1088-9051 Vol.30 N° 9 2020 págs. 1217 - 1227

Resumen

Multiple myeloma (MM) is a plasma cell neoplasm associated with a broad variety of genetic lesions. In spite of this genetic heterogeneity, MMs share a characteristic malignant phenotype whose underlying molecular basis remains poorly characterized. In the present study, we examined plasma cells from MM using a multi-epigenomics approach and demonstrated that, when compared to normal B cells, malignant plasma cells showed an extensive activation of regulatory elements, in part affecting coregulated adjacent genes. Among target genes up-regulated by this process, we found members of the NOTCH, NF-kB, MTOR signaling, and TP53 signaling pathways. Other activated genes included sets involved in osteoblast differentiation and response to oxidative stress, all of which have been shown to be associated with the MM phenotype and clinical behavior. We functionally characterized MM-specific active distant enhancers controlling the expression of thioredoxin (TXN), a major regulator of cellular redox status and, in addition, identified PRDM5 as a novel essential gene for MM. Collectively, our data indicate that aberrant chromatin activation is a unifying feature underlying the malignant plasma cell phenotype.
Autores: Aguirre, P.; Ariceta, B.; Viguria, M. C.; et al.

Título: Assessment of Minimal Residual Disease by next generation sequencing in peripheral blood as a complementary tool for personalized transplant monitoring in myeloid neoplasms

Revista: JOURNAL OF CLINICAL MEDICINE

ISSN: 2077-0383 Vol.9 N° 12 2020 págs. 3818

Resumen

Patients with myeloid neoplasms who relapsed after allogenic hematopoietic stem cell transplant (HSCT) have poor prognosis. Monitoring of chimerism and specific molecular markers as a surrogate measure of relapse is not always helpful; therefore, improved systems to detect early relapse are needed. We hypothesized that the use of next generation sequencing (NGS) could be a suitable approach for personalized follow-up post-HSCT. To validate our hypothesis, we analyzed by NGS, a retrospective set of peripheral blood (PB) DNA samples previously evaluated by high-sensitive quantitative PCR analysis using insertion/deletion polymorphisms (indel-qPCR) chimerism engraftment. Post-HCST allelic burdens assessed by NGS and chimerism status showed a similar time-course pattern. At time of clinical relapse in 8/12 patients, we detected positive NGS-based minimal residual disease (NGS-MRD). Importantly, in 6/8 patients, we were able to detect NGS-MRD at time points collected prior to clinical relapse. We also confirmed the disappearance of post-HCST allelic burden in non-relapsed patients, indicating true clinical specificity. This study highlights the clinical utility of NGS-based post-HCST monitoring in myeloid neoplasia as a complementary specific analysis to high-sensitive engraftment testing. Overall, NGS-MRD testing in PB is widely applicable for the evaluation of patients following HSCT and highly valuable to personalized early treatment intervention when mixed chimerism is detecte
Autores: Aguilera Díaz, Almudena; Vázquez Urio, Iria; Ariceta, B.; et al.

Título: Assessment of the clinical utility of four NGS panels in myeloid malignancies. Suggestions for NGS panel choice or design

Revista: PLOS ONE

ISSN: 1932-6203 Vol.15 N° 1 2020 págs. e0227986

Resumen

The diagnosis of myeloid neoplasms (MN) has significantly evolved through the last few decades. Next Generation Sequencing (NGS) is gradually becoming an essential tool to help clinicians with disease management. To this end, most specialized genetic laboratories have implemented NGS panels targeting a number of different genes relevant to MN. The aim of the present study is to evaluate the performance of four different targeted NGS gene panels based on their technical features and clinical utility. A total of 32 patient bone marrow samples were accrued and sequenced with 3 commercially available panels and 1 custom panel. Variants were classified by two geneticists based on their clinical relevance in MN. There was a difference in panel¿s depth of coverage. We found 11 discordant clinically relevant variants between panels, with a trend to miss long insertions. Our data show that there is a high risk of finding different mutations depending on the panel of choice, due both to the panel design and the data analysis method. Of note, CEBPA, CALR and FLT3 genes, remains challenging the use of NGS for diagnosis of MN in compliance with current guidelines. Therefore, conventional molecular testing might need to be kept in place for the correct diagnosis of MN for now.
Autores: Monteil, V.; Kwon, H.; Prado, P.; et al.

Título: Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2

Revista: CELL

ISSN: 0092-8674 Vol.181 N° 4 2020 págs. 905 - 913.e7

Resumen

We have previously provided the first genetic evidence that angiotensin converting enzyme 2 (ACE2) is the critical receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), and ACE2 protects the lung from injury, providing a molecular explanation for the severe lung failure and death due to SARS-CoV infections. ACE2 has now also been identified as a key receptor for SARS-CoV-2 infections, and it has been proposed that inhibiting this interaction might be used in treating patients with COVID-19. However, it is not known whether human recombinant soluble ACE2 (hrsACE2) blocks growth of SARS-CoV-2. Here, we show that clinical grade hrsACE2 reduced SARS-CoV-2 recovery from Vero cells by a factor of 1,000-5,000. An equivalent mouse rsACE2 had no effect. We also show that SARS-CoV-2 can directly infect engineered human blood vessel organoids and human kidney organoids, which can be inhibited by hrsACE2. These data demonstrate that hrsACE2 can significantly block early stages of SARS-CoV-2 infections.
Autores: Sánchez-Herrero, A.; Calvo, I. A. ; Flandes Iparraguirre, María; et al.

Título: Engineering a humanised niche to support human haematopoiesis in mice: novel opportunities in modelling cancer

Revista: CANCERS

ISSN: 2072-6694 Vol.12 N° 8 2020 págs. 2205

Resumen

Despite the bone marrow microenvironment being widely recognised as a key player in cancer research, the current animal models that represent a human haematopoietic system lack the contribution of the humanised marrow microenvironment. Here we describe a murine model that relies on the combination of an orthotopic humanised tissue-engineered bone construct (ohTEBC) with patient-specific bone marrow (BM) cells to create a humanised bone marrow (hBM) niche capable of supporting the engraftment of human haematopoietic cells. Results showed that this model supports the engraftment of human CD34+ cells from a healthy BM with human haematopoietic cells migrating into the mouse BM, human BM compartment, spleen and peripheral blood. We compared these results with the engraftment capacity of human CD34+ cells obtained from patients with multiple myeloma (MM). We demonstrated that CD34+ cells derived from a diseased BM had a reduced engraftment potential compared to healthy patients and that a higher cell dose is required to achieve engraftment of human haematopoietic cells in peripheral blood. Finally, we observed that hematopoietic cells obtained from the mobilised peripheral blood of patients yields a higher number of CD34+, overcoming this problem. In conclusion, this humanised mouse model has potential as a unique and patient-specific pre-clinical platform for the study of tumour-microenvironment interactions, including human bone and haematopoietic cells, and could, in the future, serve as a drug testing platform.
Autores: Sevilla-Movilla, S.; Arellano-Sanchez, N. ; Martinez-Moreno, M.; et al.

Título: Upregulated expression and function of the alpha 4 beta 1 integrin in multiple myeloma cells resistant to bortezomib

Revista: JOURNAL OF PATHOLOGY

ISSN: 0022-3417 Vol.252 N° 1 2020 págs. 29 - 40

Resumen

The interaction of multiple myeloma (MM) cells with the bone marrow (BM) microenvironment promotes MM cell retention, survival, and resistance to different anti-MM agents, including proteasome inhibitors (PIs) such as bortezomib (BTZ). The alpha 4 beta 1 integrin is a main adhesion receptor mediating MM cell-stroma interactions and MM cell survival, and its expression and function are downregulated by BTZ, leading to inhibition of cell adhesion-mediated drug resistance (CAM-DR) and MM cell apoptosis. Whether decreased alpha 4 beta 1 expression and activity are maintained or recovered upon development of resistance to BTZ represents an important question, as a potential rescue of alpha 4 beta 1 function could boost MM cell survival and disease progression. Using BTZ-resistant MM cells, we found that they not only rescue their alpha 4 beta 1 expression, but its levels were higher than in parental cells. Increased alpha 4 beta 1 expression in resistant cells correlated with enhanced alpha 4 beta 1-mediated cell lodging in the BM, and with disease progression. BTZ-resistant MM cells displayed enhanced NF-kappa B pathway activation relative to parental counterparts, which contributed to upregulated alpha 4 expression and to alpha 4 beta 1-dependent MM cell adhesion. These data emphasize the upregulation of alpha 4 beta 1 expression and function as a key event during resistance to BTZ in MM, which might indirectly contribute to stabilize this resistance, as stronger MM cell ...
Autores: Duran-Ferrer, M. (Autor de correspondencia); Clot, G.; Nadeu, F.; et al.

Título: The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome

Revista: NATURE CANCER

ISSN: 2662-1347 Vol.1 N° 11 2020 págs. 1066 - 1081

Resumen

We report a systematic analysis of the DNA methylation variability in 1,595 samples of normal cell subpopulations and 14 tumor subtypes spanning the entire human B-cell lineage. Differential methylation among tumor entities relates to differences in cellular origin and to de novo epigenetic alterations, which allowed us to build an accurate machine learning-based diagnostic algorithm. We identify extensive individual-specific methylation variability in silenced chromatin associated with the proliferative history of normal and neoplastic B cells. Mitotic activity generally leaves both hyper- and hypomethylation imprints, but some B-cell neoplasms preferentially gain or lose DNA methylation. We construct a DNA-methylation-based mitotic clock, called epiCMIT, whose lapse magnitude represents a strong independent prognostic variable in B-cell tumors and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracer of B-cell tumor developmental history, with implications in differential diagnosis and the prediction of clinical outcome. Martin-Subero and colleagues analyze DNA methylation patterns in B-cell tumors and their normal cells of origin, and develop epiCMIT, a methylation-based mitotic clock with prognostic relevance.
Autores: Ruiz Villalba, Adrián; Romero, JP. ; Hernández Velasco, Silvia Clara; et al.

Título: Single-Cell RNA Sequencing Analysis Reveals a Crucial Role for CTHRC1 (Collagen Triple Helix Repeat Containing 1) Cardiac Fibroblasts After Myocardial Infarction

Revista: CIRCULATION

ISSN: 0009-7322 Vol.142 N° 19 2020 págs. 1831 - 1847

Resumen

BACKGROUND: Cardiac fibroblasts (CFs) have a central role in the ventricular remodeling process associated with different types of fibrosis. Recent studies have shown that fibroblasts do not respond homogeneously to heart injury. Because of the limited set of bona fide fibroblast markers, a proper characterization of fibroblast population heterogeneity in response to cardiac damage is lacking. The purpose of this study was to define CF heterogeneity during ventricular remodeling and the underlying mechanisms that regulate CF function. METHODS: Collagen1 alpha 1-GFP (green fluorescent protein)-positive CFs were characterized after myocardial infarction (MI) by single-cell and bulk RNA sequencing, assay for transposase-accessible chromatin sequencing, and functional assays. Swine and patient samples were studied using bulk RNA sequencing. RESULTS: We identified and characterized a unique CF subpopulation that emerges after MI in mice. These activated fibroblasts exhibit a clear profibrotic signature, express high levels of Cthrc1 (collagen triple helix repeat containing 1), and localize into the scar. Noncanonical transforming growth factor-beta signaling and different transcription factors including SOX9 are important regulators mediating their response to cardiac injury. Absence of CTHRC1 results in pronounced lethality attributable to ventricular rupture. A population of CFs with a similar transcriptome was identified in a swine model of MI and in heart tissue from patients with MI and dilated cardiomyopathy. CONCLUSIONS: We report CF heterogeneity and their dynamics during the course of MI and redefine the CFs that respond to cardiac injury and participate in myocardial remodeling. Our study identifies CTHRC1 as a novel regulator of the healing scar process and a target for future translational studies.
Autores: Garcés Latre, Juan José; Simicek, M.; Vicari, M.; et al.

Título: Transcriptional profiling of circulating tumor cells in multiple myeloma: a new model to understand disease dissemination

Revista: LEUKEMIA

ISSN: 0887-6924 Vol.34 N° 2 2020 págs. 589 - 603

Resumen

The reason why a few myeloma cells egress from the bone marrow (BM) into peripheral blood (PB) remains unknown. Here, we investigated molecular hallmarks of circulating tumor cells (CTCs) to identify the events leading to myeloma trafficking into the bloodstream. After using next-generation flow to isolate matched CTCs and BM tumor cells from 32 patients, we found high correlation in gene expression at single-cell and bulk levels (r¿¿¿0.94, P¿=¿10-16), with only 55 genes differentially expressed between CTCs and BM tumor cells. CTCs overexpressed genes involved in inflammation, hypoxia, or epithelial-mesenchymal transition, whereas genes related with proliferation were downregulated in CTCs. The cancer stem cell marker CD44 was overexpressed in CTCs, and its knockdown significantly reduced migration of MM cells towards SDF1-¿ and their adhesion to fibronectin. Approximately half (29/55) of genes differentially expressed in CTCs were prognostic in patients with newly-diagnosed myeloma (n¿=¿553; CoMMpass). In a multivariate analysis including the R-ISS, overexpression of CENPF and LGALS1 was significantly associated with inferior survival. Altogether, these results help understanding the presence of CTCs in PB and suggest that hypoxic BM niches together with a pro-inflammatory microenvironment induce an arrest in proliferation, forcing tumor cells to circulate in PB and seek other BM niches to continue growing.
Autores: Dybko, J. ; Wendel, L. ; Knelange, N. ; et al.

Título: Progressive Multifocal Leukoencephalopathy (PML) after HCT - A Retrospective Study of Infectious Diseases working Party EBMT

Revista: BONE MARROW TRANSPLANTATION

ISSN: 0268-3369 Vol.55 N° SUPPL 1 2020 págs. 472 - 473
Autores: Weisel, K.; Rodríguez Otero, Paula; Davies, F. ; et al.

Título: Matching-adjusted indirect comparisons of efficacy outcomes for idecabtagene vicleucel (ide-cel; bb2121) from the KarMMa study vs selinexor plus dexamethasone (Sd; STORM part 2) and belantamab mafodotin (BM; DREAMM-2)

Revista: ONCOLOGY RESEARCH AND TREATMENT

ISSN: 2296-5270 Vol.43 N° SUPPL 4 2020 págs. 118 - 118
Autores: Richardson, P. G.; Vangsted, A. J.; Ramasamy, K.; et al.

Título: First-in-human phase I study of the novel CELMoD agent CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).

Revista: JOURNAL OF CLINICAL ONCOLOGY

ISSN: 0732-183X Vol.38 N° 15 2020
Autores: Kwon, M. ; Bailen, R. ; Cascon, M. J. P. ; et al.

Título: Post-transplant Cyclophosphamide after Matched Sibling and Matched Unrelated Compared to Haploidentical Donor Transplants in Patients with Acute Myeloid Leukemia, a Study on Behalf of Geth

Revista: BONE MARROW TRANSPLANTATION

ISSN: 0268-3369 Vol.55 N° SUPPL 1 2020 págs. 342 - 343
Autores: Ordóñez Ciriza, Raquel; Martínez Calle, Nicolás; Aguirre Ena, Xabier (Autor de correspondencia); et al.

Título: DNA Methylation of Enhancer Elements in Myeloid Neoplasms: Think Outside the Promoters?

Revista: CANCERS

ISSN: 2072-6694 Vol.11 N° 10 2019

Resumen

Gene regulation through DNA methylation is a well described phenomenon that has a prominent role in physiological and pathological cell-states. This epigenetic modification is usually grouped in regions denominated CpG islands, which frequently co-localize with gene promoters, silencing the transcription of those genes. Recent genome-wide DNA methylation studies have challenged this paradigm, demonstrating that DNA methylation of regulatory regions outside promoters is able to influence cell-type specific gene expression programs under physiologic or pathologic conditions. Coupling genome-wide DNA methylation assays with histone mark annotation has allowed for the identification of specific epigenomic changes that affect enhancer regulatory regions, revealing an additional layer of complexity to the epigenetic regulation of gene expression. In this review, we summarize the novel evidence for the molecular and biological regulation of DNA methylation in enhancer regions and the dynamism of these changes contributing to the fine-tuning of gene expression. We also analyze the contribution of enhancer DNA methylation on the expression of relevant genes in acute myeloid leukemia and chronic myeloproliferative neoplasms. The characterization of the aberrant enhancer DNA methylation provides not only a novel pathogenic mechanism for different tumors but also highlights novel potential therapeutic targets for myeloid derived neoplasms.
Autores: Carazo Melo, Fernando; Romero Riojas, Juan Pablo; Rubio Díaz-Cordoves, Ángel (Autor de correspondencia)

Título: Upstream analysis of alternative splicing: a review of computational approaches to predict context-dependent splicing factors

Revista: BRIEFINGS IN BIOINFORMATICS

ISSN: 1467-5463 Vol.20 N° 4 2019 págs. 1358 - 1375

Resumen

Alternative splicing (AS) has shown to play a pivotal role in the development of diseases, including cancer. Specifically, all the hallmarks of cancer (angiogenesis, cell immortality, avoiding immune system response, etc.) are found to have a counterpart in aberrant splicing of key genes. Identifying the context-specific regulators of splicing provides valuable information to find new biomarkers, as well as to define alternative therapeutic strategies. The computational models to identify these regulators are not trivial and require three conceptual steps: the detection of AS events, the identification of splicing factors that potentially regulate these events and the contextualization of these pieces of information for a specific experiment. In this work, we review the different algorithmic methodologies developed for each of these tasks. Main weaknesses and strengths of the different steps of the pipeline are discussed. Finally, a case study is detailed to help the reader be aware of the potential and limitations of this computational approach.
Autores: Herrero D; Cañón S; Pelacho Samper, Beatriz; et al.

Título: Bmi1-Progenitor Cell Ablation Impairs the Angiogenic Response to Myocardial Infarction (vol 38, pg 2160, 2018)

Revista: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY

ISSN: 1079-5642 Vol.39 N° 3 2019 págs. E106 - E106
Autores: Puig, N. ; Paiva, Bruno (Autor de correspondencia); Lasa Ventura, Marta; et al.

Título: Flow cytometry for fast screening and automated risk assessment in systemic light-chain amyloidosis

Revista: LEUKEMIA

ISSN: 0887-6924 Vol.33 N° 5 2019 págs. 1256 - 1267

Resumen

Early diagnosis and risk stratification are key to improve outcomes in light-chain (AL) amyloidosis. Here we used multidimensional-flow-cytometry (MFC) to characterize bone marrow (BM) plasma cells (PCs) from a series of 166 patients including newly-diagnosed AL amyloidosis (N = 9 4) , MGUS (N = 20) and multiple myeloma (MM, N = 52) vs. healthy adults (N= 30). MFC detected clonality in virtually all AL amyloidosis (99%) patients. Furthermore, we developed an automated risk-stratification system based on BMPCs features, with independent prognostic impact on progression-free and overall survival of AL amyloidosis patients (hazard ratio: >= 2.9;P <= .03). Simultaneous assessment of the clonal PCs immunophenotypic protein expression profile and the BM cellular composition, mapped AL amyloidosis in the crossroad between MGUS and MM; however, lack of homogenously-positive CD56 expression, reduction of B-cell precursors and a predominantly-clonal PC compartment in the absence of an MM-like tumor PC expansion, emerged as hallmarks of AL amyloidosis (ROC-AUC = 0.74;P < .001), and might potentially be used as biomarkers for the identification of MGUS and MM patients, who are candidates for monitoring pre-symptomatic organ damage related to AL amyloidosis. Altogether, this study addressed the need for consensus on how to use flow cytometry in AL amyloidosis, and proposes a standardized MFCbased automated risk classification ready for implementation in clinical practice.
Autores: Paya-Milans, M.; Poza-Viejo, L.; San Martín Úriz, Patxi; et al.

Título: Genome-wide analysis of the H3K27me3 epigenome and transcriptome in Brassica rapa

Revista: GIGASCIENCE

ISSN: 2047-217X Vol.8 N° 12 2019 págs. giz147

Resumen

BACKGROUND: Genome-wide maps of histone modifications have been obtained for several plant species. However, most studies focus on model systems and do not enforce FAIR data management principles. Here we study the H3K27me3 epigenome and associated transcriptome of Brassica rapa, an important vegetable cultivated worldwide. FINDINGS: We performed H3K27me3 chromatin immunoprecipitation followed by high-throughput sequencing and transcriptomic analysis by 3'-end RNA sequencing from B. rapa leaves and inflorescences. To analyze these data we developed a Reproducible Epigenomic Analysis pipeline using Galaxy and Jupyter, packaged into Docker images to facilitate transparency and reuse. We found that H3K27me3 covers roughly one-third of all B. rapa protein-coding genes and its presence correlates with low transcript levels. The comparative analysis between leaves and inflorescences suggested that the expression of various floral regulatory genes during development depends on H3K27me3. To demonstrate the importance of H3K27me3 for B. rapa development, we characterized a mutant line deficient in the H3K27 methyltransferase activity. We found that braA.clf mutant plants presented pleiotropic alterations, e.g., curly leaves due to increased expression and reduced H3K27me3 levels at AGAMOUS-like loci. CONCLUSIONS: We characterized the epigenetic mark H3K27me3 at genome-wide levels and provide genetic evidence for its relevance in B. rapa development. Our work reveals the epigenomic landscape of H3K27me3 in B. rapa and provides novel genomics datasets and bioinformatics analytical resources. We anticipate that this work will lead the way to further epigenomic studies in the complex genome of Brassica crops.
Autores: Moreno Narro, Laura; Pérez Ruiz, Cristina; Zabaleta Azpiroz, Aintzane; et al.

Título: The mechanism of action of the anti-CD38 monoclonal antibody isatuximab in multiple myeloma

Revista: CLINICAL CANCER RESEARCH

ISSN: 1078-0432 Vol.25 N° 10 2019 págs. 3176 - 3187

Resumen

Purpose: Knowledge about the mechanism of action (MoA) of monoclonal antibodies (mAb) is required to understand which patients with multiple myeloma (MM) benefit the most from a given mAb, alone or in combination therapy. Although there is considerable research about daratumumab, knowledge about other anti-CD38 mAbs remains scarce. Experimental Design: We performed a comprehensive analysis of the MoA of isatuximab. Results: Isatuximab induces internalization of CD38 but not its significant release from MMcell surface. In addition, we uncovered an association between levels of CD38 expression and different MoA: (i) Isatuximab was unable to induce direct apoptosis on MM cells with CD38 levels closer to those in patients with MM, (ii) isatuximab sensitized CD38(hi) MMcells to bortezomib plus dexamethasone in the presence of stroma, (iii) antibody-dependent cellular cytotoxicity (ADCC) was triggered by CD38(lo) and CD38(hi) tumor plasma cells (PC), (iv) antibody-dependent cellular phagocytosis (ADCP) was triggered only by CD38(hi) MM cells, whereas (v) complement-dependent cytotoxicity could be triggered in less than half of the patient samples (those with elevated levels of CD38). Furthermore, we showed that isatuximab depletes CD38(hi) B-lymphocyte precursors and natural killer (NK) lymphocytes ex vivo-the latter through activation followed by exhaustion and eventually phagocytosis. Conclusions: This study provides a framework to understand response determinants in patients treated with isatuximab based on the number of MoA triggered by CD38 levels of expression, and for the design of effective combinations aimed at capitalizing disrupted tumor-stroma cell protection, augmenting NK lymphocyte-mediated ADCC, or facilitating ADCP in CD38(lo) MM patients.
Autores: Aguirre Ena, Xabier (Autor de correspondencia); Meydan, C.; Jiang, Y. W.; et al.

Título: Long non-coding RNAs discriminate the stages and gene regulatory states of human humoral immune response

Revista: NATURE COMMUNICATIONS

ISSN: 2041-1723 Vol.10 2019 págs. 821

Resumen

lncRNAs make up a majority of the human transcriptome and have key regulatory functions. Here we perform unbiased de novo annotation of transcripts expressed during the human humoral immune response to find 30% of the human genome transcribed during this process, yet 58% of these transcripts manifest striking differential expression, indicating an lncRNA phylogenetic relationship among cell types that is more robust than that of coding genes. We provide an atlas of lncRNAs in naive and GC B-cells that indicates their partition into ten functionally categories based on chromatin features, DNase hypersensitivity and transcription factor localization, defining lncRNAs classes such as enhancer-RNAs (eRNA), bivalent-lncRNAs, and CTCF-associated, among others. Specifically, eRNAs are transcribed in 8.6% of regular enhancers and 36.5% of super enhancers, and are associated with coding genes that participate in critical immune regulatory pathways, while plasma cells have uniquely high levels of circular-RNAs accounted for by and reflecting the combinatorial clonal state of the Immunoglobulin loci.
Autores: Martínez Calle, Nicolás; Pascual, M.; Ordóñez Ciriza, Raquel; et al.

Título: Epigenomic profiling of myelofibrosis reveals widespread DNA methylation changes in enhancer elements and ZFP36L1 as a potential tumor suppressor gene that is epigenetically regulated

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 N° 8 2019 págs. 1572 - 1579

Resumen

In this study we interrogated the DNA methylome of myelofibrosis patients using high-density DNA methylation arrays. We detected 35,215 differentially methylated CpG, corresponding to 10,253 genes, between myelofibrosis patients and healthy controls. These changes were present both in primary and secondary myelofibrosis, which showed no differences between them. Remarkably, most differentially methylated CpG were located outside gene promoter regions and showed significant association with enhancer regions. This aberrant enhancer hypermethylation was negatively correlated with the expression of 27 genes in the myelofibrosis cohort. Of these, we focused on the ZFP36L1 gene and validated its decreased expression and enhancer DNA hypermethylation in an independent cohort of patients and myeloid cell-lines. In vitro reporter assay and 5'-azacitidine treatment confirmed the functional relevance of hypermethylation of ZFP36L1 enhancer. Furthermore, in vitro rescue of ZFP36L1 expression had an impact on cell proliferation and induced apoptosis in SET-2 cell line indicating a possible role of ZFP36L1 as a tumor suppressor gene in myelofibrosis. Collectively, we describe the DNA methylation profile of myelofibrosis, identifying extensive changes in enhancer elements and revealing ZFP36L1 as a novel candidate tumor suppressor gene.
Autores: Naqvi, K.; Sasaki, K.; Montalban-Bravo, G.; et al.

Título: Clonal hematopoiesis of indeterminate potential-associated mutations and risk of comorbidities in patients with myelodysplastic syndrome

Revista: CANCER

ISSN: 0008-543X Vol.125 N° 13 2019 págs. 2233 - 2241

Resumen

Background: Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations increase the risk of atherosclerotic heart disease. Comorbidities significantly impact the prognosis of patients with myelodysplastic syndromes (MDS). The objective of this study was to determine the association and impact of CHIP mutations with comorbidities in patients with MDS. Methods: This retrospective analysis of 566 consecutive patients with MDS was conducted at The University of Texas MD Anderson Cancer Center from August 2013 to December 2016. The 27-item Adult Comorbidity Evaluation (ACE-27) scale was used to assess the severity of comorbid conditions. Next-generation sequencing was used to detect the presence of CHIP mutations in bone marrow aspirates. Spearman correlations and logistic regression analyses were used to determine the association between mutations and comorbidities. Results: Mutations in the genes tet methylcytosine dioxygenase 2 (TET2), ASXL transcriptional regulator 1 (ASXL1), DNA methyltransferase 3¿ (DNMT3A), Janus kinase 2 (JAK2), and tumor protein 53 (TP53) were noted in 20%, 18%, 9%, 2%, and 21% of patients, respectively. Patients with DNMT3A and JAK2 mutations had higher likelihoods of a prior history of myocardial infarction (odds ratio, 2.62; P = .03) and veno-occlusive disease (odds ratio, 6.48; P = .02), respectively. TP53 mutation was associated with a prior history of malignancy. Patients with TET2 mutation had no association with any comorbidity. A prognostic model including the revised International Prognostic Scoring System classification, the ACE-27 score, and TP53 mutation status (the I-RAT model) predicted median overall survival. Conclusions: In patients with MDS, the presence of CHIP-associated mutations is associated with comorbidities. DNMT3A and JAK2 mutations were associated with higher likelihoods of prior myocardial infarction and thrombotic events. There was no association between comorbidity and TET2 mutation. Incorporating the revised International Prognostic Scoring System classification with the ACE-27 and TP53 mutation status improved outcome prediction in patients with MDS.
Autores: Bárcena Varela, Marina; Caruso, S. ; Llerena, S. ; et al.

Título: Dual targeting of histone methyltransferase G9a and DNA-methyltransferase 1 for the treatment of experimental hepatocellular carcinoma

Revista: HEPATOLOGY

ISSN: 0270-9139 Vol.69 N° 2 2019 págs. 587 - 603

Resumen

Epigenetic modifications such as DNA and histone methylation functionally cooperate in fostering tumor growth, including that of hepatocellular carcinoma (HCC). Pharmacological targeting of these mechanisms may open new therapeutic avenues. We aimed to determine the therapeutic efficacy and potential mechanism of action of our dual G9a histone-methyltransferase and DNA-methyltransferase 1 (DNMT1) inhibitor in human HCC cells and their crosstalk with fibrogenic cells. The expression of G9a and DNMT1, along with that of their molecular adaptor ubiquitin-like with PHD and RING finger domains-1 (UHRF1), was measured in human HCCs (n = 268), peritumoral tissues (n = 154), and HCC cell lines (n = 32). We evaluated the effect of individual and combined inhibition of G9a and DNMT1 on HCC cell growth by pharmacological and genetic approaches. The activity of our lead compound, CM-272, was examined in HCC cells under normoxia and hypoxia, human hepatic stellate cells and LX2 cells, and xenograft tumors formed by HCC or combined HCC+LX2 cells. We found a significant and correlative overexpression of G9a, DNMT1, and UHRF1 in HCCs in association with poor prognosis. Independent G9a and DNMT1 pharmacological targeting synergistically inhibited HCC cell growth. CM-272 potently reduced HCC and LX2 cells proliferation and quelled tumor growth, particularly in HCC+LX2 xenografts. Mechanistically, CM-272 inhibited the metabolic adaptation of HCC cells to hypoxia and induced a differentiated phenotype in HCC and fibrogenic cells. The expression of the metabolic tumor suppressor gene fructose-1,6-bisphosphatase (FBP1), epigenetically repressed in HCC, was restored by CM-272. Conclusion: Combined targeting of G9a/DNMT1 with compounds such as CM-272 is a promising strategy for HCC treatment. Our findings also underscore the potential of differentiation therapy in HCC.
Autores: San José Enériz, Edurne; Gimenez Camino, Naroa; Aguirre Ena, Xabier; et al.

Título: HDAC inhibitors in acute myeloid leukemia

Revista: CANCERS

ISSN: 2072-6694 Vol.11 N° 11 2019 págs. 1794

Resumen

Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases (HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat, and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather in combination with other drugs. In this review, we discuss the rationale for the use of different HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are some encouraging data from treatment with the HDACi Pracinostat in combination with DNA demethylating agents.
Autores: Redondo, A. M.; Valcarce, D. ; Gonzalez-Rodriguez, A. P. ; et al.

Título: Bendamustine as part of conditioning of autologous stem cell transplantation in patients with aggressive lymphoma: a phase 2 study from the GELTAMO group

Revista: BRITISH JOURNAL OF HAEMATOLOGY

ISSN: 0007-1048 Vol.184 N° 5 2019 págs. 797 - 807

Resumen

We conducted a phase 2 trial to evaluate the safety and efficacy of bendamustine instead of BCNU (carmustine) in the BEAM (BCNU, etoposide, cytarabine and melphalan) regimen (BendaEAM) as conditioning for autologous stem-cell transplantation (ASCT) in patients with aggressive lymphomas. The primary endpoint was 3-year progression-free survival (PFS). Sixty patients (median age 55 [28-71] years) were included. All patients (except one who died early) engrafted after a median of 11 (9-72) and 14 (4-53) days to achieve neutrophil and platelet counts of >0.5 x 10(9)/l and >20 x 10(9)/l, respectively. Non-relapse mortality at 100 days and 1 year were 3.3% and 6.7%, respectively. With a median follow-up of 67 (40-77) months, the estimated 3-year PFS and overall survival (OS) were 58% and 75%, respectively. Patients in partial response at study entry had significantly worse PFS and OS than patients who underwent ASCT in complete metabolic remission, and this was the only prognostic factor associated with both PFS (Relative risk [RR], 0.27 [95% confidence interval {CI} [0.12-0.56]) and OS (RR, 0.40 [95% CI 0.17-0.97]) in the multivariate analysis. BendaEAM conditioning is therefore a feasible and effective regimen in patients with aggressive lymphomas. However, patients not in complete metabolic remission at the time of transplant had poorer survival and so should be considered for alternative treatment strategies.
Autores: Segovia, C.; San José Enériz, Edurne; Munera-Maravilla, E.; et al.

Título: Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression

Revista: NATURE MEDICINE

ISSN: 1078-8956 Vol.25 N° 7 2019 págs. 1073 - 1081

Resumen

Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances(1,2). Recent molecular characterization has defined new (epi) genetic drivers and potential targets for bladder cancer(3,4). The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients(5-8). Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (Pten(loxP/loxP); Trp53(loxP/loxP); Rb1(loxP/loxP); Rbl1(-/-)) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.
Autores: Ariceta-Ganuza, B.; Aguilera Díaz, Almudena; Vázquez Urio, Iria; et al.

Título: La secuenciación a baja cobertura del genoma completo para la detección de variantes en el número de copias en leucemia linfática crónica supera a la FISH en alcance y resolución

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 N° S3 2019 págs. 174 - 174
Autores: Carrasco-Leon, A. ; Ezponda Itoiz, Teresa; Meydan, C. ; et al.

Título: Role of lncRNAs as prognostic factor and potential therapeutic target in multiple myeloma

Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA

ISSN: 2152-2650 Vol.19 N° 10 2019 págs. E354 - E355
Autores: San José Enériz, Edurne; Gimenez Camino, Naroa; Rabal Gracia, María Obdulia; et al.

Título: Differentiation therapy with novel epigenetic inhibitors in acute myeloid leukemia

Revista: BLOOD

ISSN: 0006-4971 Vol.134 N° Supl. 1 2019
Autores: Carazo Melo, Fernando; San José Enériz, Edurne; Garate Iturriagagoitia, Leire; et al.

Título: A computational based approach for identification and validation of gene mutations As surrogate markers of gene essentiality in acute myeloid leukemia

Revista: BLOOD

ISSN: 0006-4971 Vol.134 N° supl.1 2019
Autores: Colyn, L.; Alvarez-Sola, G.; Latasa Sada, María Ujué; et al.

Título: Dual targeting of G9a and DNM-methyltransferase-1 for the treatment of experimental cholangiocarcinoma

Revista: JOURNAL OF HEPATOLOGY (ONLINE)

ISSN: 0168-8278 Vol.70 N° Supl. 1 2019 págs. E27 - E28
Autores: Carazo Melo, Fernando; San José Enériz, Edurne; Garate, L.; et al.

Título: Mutaciones génicas como marcador subrogado de la esencialidad génica y nuevas dianas terapéuticas para la leucemia aguda mieloblástica

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 2019 págs. 49 - 49
Autores: San José Enériz, Edurne; Gimenez-Camino, N.; Rabal, O. ; et al.

Título: Terapia epigenética diferenciadora e innovadora para la cura de la leucemia mieloide aguda

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 2019 págs. 242 - 242
Autores: Ezponda Itoiz, Teresa; Romero Riojas, Juan Pablo; Ainciburu Fernandez, Marina; et al.

Título: Alteraciones transcripcionales de las células madre hematopoyéticas en el eje envejecimiento-síndromes mielodisplásicos

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 2019 págs. 88 - 88
Autores: Aguilera Díaz, Almudena; Vázquez Urio, Iria; Ariceta, B.; et al.

Título: Comparación de cuatro paneles ngs para neoplasias mieloides: carácterísticas técnicas y utilidad clínica

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 N° S3 2019 págs. 110 - 110
Autores: Alameda Serrano, Daniel; Puig, N. ; Cedena, M. T. ; et al.

Título: Explorando la celula de origen y los programas transcripcionales patologicos en mieloma multiple (mm) y amiloidosis de cadena ligera (al) mediante la diseccion del desarrollo de la celula plasmatica (cp) normal

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 2019 págs. 12 - 12
Autores: Vinado-Solanas, A. C. ; Calvo Arnedo, Isabel; Cenzano Armendariz, Itziar; et al.

Título: El nicho mesenquimal de la médula ósea regula el balance redox en células madre de la leucemia mieloide aguda

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 2019 págs. 2 - 2
Autores: Blasco-Iturri, Z.; Vázquez Urio, Iria; Ariceta, B.; et al.

Título: Utilidad clínica de un panel NGS en la monitorización de pacientes con leucemia mieloide aguda

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 N° S3 2019 págs. 56 - 57
Autores: Sargas, C.; Ayala, R. ; Chillon, C. ; et al.

Título: Multicentre implementation of next generation sequencing to acute myeloid leukemia patients in PETHEMA spanish collaborative group

Revista: ANNALS OF HEMATOLOGY

ISSN: 0939-5555 Vol.98 N° Suppl. 1 2019 págs. S38 - S39
Autores: Pena Carbó, Esther; Munoz, R. G.; López Díaz de Cerio, Ascensión; et al.

Título: La infusión de linfocitos efectores autólogos en combinación con rituximab de mantenimiento es segura y eficaz. Resultados del ensayo clínico fase ii lfnk

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 2019 págs. 3 - 4
Autores: Ariceta-Ganuza, B.; Mañú Arruti, Amagoia; Larráyoz Ilundáin, María José; et al.

Título: Detección de alteraciones clínicamente relevantes en leucemia linfáticacrónica mediante un panel NGS

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 N° S3 2019 págs. 249 - 249
Autores: Ordóñez Ciriza, Raquel; Kulis, M. ; Russinol, N. ; et al.

Título: Caracterización de los mecanismos epigenéticos implicados en la patogénesis del mieloma múltiple y su papel en la respuesta al estrés oxidativo

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 N° S3 2019 págs. 19 - 20
Autores: Aguilera Díaz, Almudena; Palomino-Echeverria, S.; Vázquez Urio, Iria; et al.

Título: Utilidad de cinco tejidos para discriminar variantes somáticas y germinales en neoplasias mieloides

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 N° S3 2019 págs. 72 - 73
Autores: Riego Repullo, Victoria; Blasco-Iturri, Z. ; Villar Fernández, Sara; et al.

Título: Impacto clínico de los paneles de NGS en patología mieloide: LMA y SMD ¿son realmente útiles?

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 N° S3 2019 págs. 110 - 111
Autores: Carrasco Leon, Arantxa; Ezponda Itoiz, Teresa; Meydan, C.; et al.

Título: Análisis de la complejidad y heterogeneidad del transcriptoma de los Lncrnas y su relevancia en el mieloma múltiple

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 2019 págs. 11 - 11
Autores: Aguirre-Ruiz, P. ; Viguria, M. C.; Blasco-Iturri, Z. ; et al.

Título: Determinación de enfermedad mínima residual molecular en sangre periférica mediante NGS como nueva herramienta en el seguimiento posttrasplante alogénico de progenitores hematopoyéticos

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 N° S3 2019 págs. 329 - 330
Autores: Prieto-Conde, M. I. ; Vázquez Urio, Iria; Fernández Mercado, Marta; et al.

Título: Nueva estrategia de secuenciación masiva para la detección simultánea de mutaciones génicas y variaciones del número de copias en neoplasias mieloides

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.104 N° S3 2019 págs. 266 - 266
Autores: Martínez Calle, Nicolás (Autor de correspondencia); Rodríguez Otero, Paula; Villar Fernández, Sara; et al.

Título: Anti-PD1 associated fulminant myocarditis after a single pembrolizumab dose: the role of occult pre-existing autoimmunity

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.103 N° 7 2018 págs. E318 - E321
Autores: Herrero, D.; Canon, S. ; Pelacho Samper, Beatriz; et al.

Título: Bmi1-Progenitor cell ablation impairs the angiogenic response to myocardial infarction

Revista: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY

ISSN: 1079-5642 Vol.38 N° 9 2018 págs. 2160 - 2173

Resumen

Objective Cardiac progenitor cells reside in the heart in adulthood, although their physiological relevance remains unknown. Here, we demonstrate that after myocardial infarction, adult Bmi1(+) (B lymphoma Mo-MLV insertion region 1 homolog [PCGF4]) cardiac cells are a key progenitor-like population in cardiac neovascularization during ventricular remodeling. Approach and Results These cells, which have a strong in vivo differentiation bias, are a mixture of endothelial- and mesenchymal-related cells with in vitro spontaneous endothelial cell differentiation capacity. Genetic lineage tracing analysis showed that heart-resident Bmi1(+) progenitor cells proliferate after acute myocardial infarction and differentiate to generate de novo cardiac vasculature. In a mouse model of induced myocardial infarction, genetic ablation of these cells substantially deteriorated both heart angiogenesis and the ejection fraction, resulting in an ischemic-dilated cardiac phenotype. Conclusions These findings imply that endothelial-related Bmi1(+) progenitor cells are necessary for injury-induced neovascularization in adult mouse heart and highlight these cells as a suitable therapeutic target for preventing dysfunctional left ventricular remodeling after injury.
Autores: Rabal Gracia, María Obdulia; Sánchez Arias, Juan Antonio; San José Enériz, Edurne; et al.

Título: Detailed exploration around 4-aminoquinolines chemical space to navigate the lysine methyltransferase G9a and DNA methyltransferase biological spaces

Revista: JOURNAL OF MEDICINAL CHEMISTRY

ISSN: 0022-2623 Vol.61 N° 15 2018 págs. 6546-6573

Resumen

Epigenetic regulators that exhibit aberrant enzymatic activities or expression profiles are potential therapeutic targets for cancers. Specifically, enzymes responsible for methylation at histone-3 lysine-9 (like G9a) and aberrant DNA hypermethylation (DNMTs) have been implicated in a number of cancers. Recently, molecules bearing a 4-aminoquinoline scaffold were reported as dual inhibitors of these targets and showed a significant in vivo efficacy in animal models of hematological malignancies. Here, we report a detailed exploration around three growing vectors born by this chemotype. Exploring this chemical space led to the identification of features to navigate G9a and DNMT1 biological spaces: not only their corresponding exclusive areas, selective compounds, but also common spaces. Thus, we identified from selective G9a and first-in-class DNMT1 inhibitors, >1 log unit between their IC50 values, with IC50 < 25 nM (e.g., 43 and 26, respectively) to equipotent inhibitors with IC50 < 50 nM for both targets (e.g., 13). Their ADME/Tox profiling and antiproliferative efficacies, versus some cancer cell lines, are also reported.
Autores: Rabal Gracia, María Obdulia; San José Enériz, Edurne; Aguirre Ena, Xabier; et al.

Título: Discovery of reversible DNA methyltransferase and lysine methyltransferase G9a inhibitors with antitumoral in vivo efficacy

Revista: JOURNAL OF MEDICINAL CHEMISTRY

ISSN: 0022-2623 Vol.61 N° 15 2018 págs. 6518-6545

Resumen

Using knowledge- and structure-based approaches, we designed and synthesized reversible chemical probes that simultaneously inhibit the activity of two epigenetic targets, histone 3 lysine 9 methyltransferase (G9a) and DNA methyltransferases (DNMT), at nanomolar ranges. Enzymatic competition assays confirmed our design strategy: substrate competitive inhibitors. Next, an initial exploration around our hit 11 was pursued to identify an adequate tool compound for in vivo testing. In vitro treatment of different hematological neoplasia cell lines led to the identification of molecules with clear antiproliferative efficacies (GI50 values in the nanomolar range). On the basis of epigenetic functional cellular responses (levels of lysine 9 methylation and 5-methylcytosine), an acceptable therapeutic window (around 1 log unit) and a suitable pharmacokinetic profile, 12 was selected for in vivo proof-of-concept ( Nat. Commun. 2017 , 8 , 15424 ). Herein, 12 achieved a significant in vivo efficacy: 70% overall tumor growth inhibition of a human acute myeloid leukemia (AML) xenograft in a mouse model.
Autores: Carazo Melo, Fernando; Romero Riojas, Juan Pablo; Rubio Díaz-Cordoves, Ángel (Autor de correspondencia)

Título: Upstream analysis of alternative splicing: a review of computational approaches to predict context-dependent splicing factors.

Revista: BRIEFINGS IN BIOINFORMATICS

ISSN: 1477-4054 2018

Resumen

Alternative splicing (AS) has shown to play a pivotal role in the development of diseases, including cancer. Specifically, all the hallmarks of cancer (angiogenesis, cell immortality, avoiding immune system response, etc.) are found to have a counterpart in aberrant splicing of key genes. Identifying the context-specific regulators of splicing provides valuable information to find new biomarkers, as well as to define alternative therapeutic strategies. The computational models to identify these regulators are not trivial and require three conceptual steps: the detection of AS events, the identification of splicing factors that potentially regulate these events and the contextualization of these pieces of information for a specific experiment. In this work, we review the different algorithmic methodologies developed for each of these tasks. Main weaknesses and strengths of the different steps of the pipeline are discussed. Finally, a case study is detailed to help the reader be aware of the potential and limitations of this computational approach.
Autores: Martín Moreno, Paloma Leticia (Autor de correspondencia); Rifón Roca, José Juan; Errasti Goenaga, Pedro

Título: Efficacy of the combination of immunoadsorption and rituximab for treatment in a case of severe focal and segmental glomerulosclerosis recurrence after renal transplantation

Revista: BLOOD PURIFICATION

ISSN: 0253-5068 Vol.46 N° 2 2018 págs. 90 - 93

Resumen

Background/Aims: We present a case of a male patient with severe recurrence of focal and segmental glomerulosclerosis (FSGS) after transplant. Methods: Before the transplant he was treated with plasma exchange. Massive proteinuria was detected post-transplantation and plasma exchanges were performed without response. We administered 5 doses of Rituximab (375 mg/m2) and partial remission was achieved. Proteinuria relapse occurred 1 year post-transplant, so Immunoadsorption (IA) was started instead of plasma exchange with reduction of proteinuria. Later, 2 new episodes of proteinuria relapse were detected and treated by increasing the number of IA sessions and administering new cycles of Rituximab. After achieving partial remission, IA was reduced to one session every 7-10 days as maintenance therapy. Results: Despite the fact of the severe recurrence, renal function and proteinuria remain stable over 8 years after the transplantation was performed. Conclusion: Combination of maintenance IA and cycles of Rituximab is an effective treatment for aggressive forms of FSGS recurrence after renal transplantation. (C) 2018 S. Karger AG, Basel
Autores: Rutherford, S. C.; Fachel, A. A.; Li, S. ; et al.

Título: Extracellular vesicles in DLBCL provide abundant clues to aberrant transcriptional programming and genomic alterations

Revista: BLOOD

ISSN: 0006-4971 Vol.132 N° 7 2018 págs. e13 - e23

Resumen

The biological role of extracellular vesicles (EVs) in diffuse large B-cell lymphoma (DLBCL) initiation and progression remains largely unknown. We characterized EVs secreted by 5 DLBCL cell lines, a primary DLBCL tumor, and a normal control B-cell sample, optimized their purification, and analyzed their content. We found that DLBCLs secreted large quantities of CD63, Alix, TSG101, and CD81 EVs, which can be extracted using an ultracentrifugation-based method and traced by their cell of origin surface markers. We also showed that tumor-derived EVs can be exchanged between lymphoma cells, normal tonsillar cells, and HK stromal cells. We then examined the content of EVs, focusing on isolation of high-quality total RNA. Wesequenced the total RNA and analyzed the nature of RNA species, including coding and noncoding RNAs. We compared whole-cell and EV-derived RNA composition in benign and malignant B cells and discovered that transcripts from EVs were involved in many critical cellular functions. Finally, we performed mutational analysis and found that mutations detected in EVs exquisitely represented mutations in the cell of origin. These results enhance our understanding and enable future studies of the role that EVs may play in the pathogenesis of DLBCL, particularly with regards to the exchange of genomic information. Current findings open a new strategy for liquid biopsy approaches in disease monitoring.
Autores: Montalbán-Bravo, G. (Autor de correspondencia); Takahashi, K.; Patel, K.; et al.

Título: Impact of the number of mutations in survival and response outcomes to hypomethylating agents in patients with myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms

Revista: ONCOTARGET

ISSN: 1949-2553 Vol.9 N° 11 2018 págs. 9714 - 9727

Resumen

The prognostic and predictive value of sequencing analysis in myelodysplastic syndromes (MDS) has not been fully integrated into clinical practice. We performed whole exome sequencing (WES) of bone marrow samples from 83 patients with MDS and 31 with MDS/MPN identifying 218 driver mutations in 31 genes in 98 (86%) patients. A total of 65 (57%) patients received therapy with hypomethylating agents. By univariate analysis, mutations in BCOR, STAG2, TP53 and SF3B1 significantly influenced survival. Increased number of mutations (¿ 3), but not clonal heterogeneity, predicted for shorter survival and LFS. Presence of 3 or more mutations also predicted for lower likelihood of response (26 vs 50%, p = 0.055), and shorter response duration (3.6 vs 26.5 months, p = 0.022). By multivariate analysis, TP53 mutations (HR 3.1, CI 1.3-7.5, p = 0.011) and number of mutations (¿ 3) (HR 2.5, CI 1.3-4.8, p = 0.005) predicted for shorter survival. A novel prognostic model integrating this mutation data with IPSS-R separated patients into three categories with median survival of not reached, 29 months and 12 months respectively (p < 0.001) and increased stratification potential, compared to IPSS-R, in patients with high/very-high IPSS-R. This model was validated in a separate cohort of 413 patients with untreated MDS. Although the use of WES did not provide significant more information than that obtained with targeted sequencing, our findings indicate that increased number of mutations is an inde
Autores: Sanoja-Flores, L.; Flores-Montero, J. ; Garcés Latre, Juan José; et al.

Título: Next generation flow for minimally-invasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC)

Revista: BLOOD CANCER JOURNAL

ISSN: 2044-5385 Vol.8 2018 págs. 117

Resumen

Here, we investigated for the first time the frequency and number of circulating tumor plasma cells (CTPC) in peripheral blood (PB) of newly diagnosed patients with localized and systemic plasma cell neoplasms (PCN) using next-generation flow cytometry (NGF) and correlated our findings with the distinct diagnostic and prognostic categories of the disease. Overall, 508 samples from 264 newly diagnosed PCN patients, were studied. CTPC were detected in PB of all active multiple myeloma (MM; 100%), and smoldering MM (SMM) patients (100%), and in more than half (59%) monoclonal gammopathy of undetermined significance (MGUS) cases (p < 0.0001); in contrast, CTPC were present in a small fraction of solitary plasmacytoma patients (18%). Higher numbers of CTPC in PB were associated with higher levels of BM infiltration and more adverse prognostic features, together with shorter time to progression from MGUS to MM (p < 0.0001) and a shorter survival in MM patients with active disease requiring treatment (p <= 0.03). In summary, the presence of CTPC in PB as assessed by NGF at diagnosis, emerges as a hallmark of disseminated PCN, higher numbers of PB CTPC being strongly associated with a malignant disease behavior and a poorer outcome of both MGUS and MM.
Autores: Beekman , R; Chapaprieta , V; Russiñol, N; et al.

Título: The reference epigenome and regulatory chromatin landscape of chronic lymphocytic leukemia.

Revista: NATURE MEDICINE

ISSN: 1078-8956 Vol.24 N° 6 2018 págs. 868-880

Resumen

Chronic lymphocytic leukemia (CLL) is a frequent hematological neoplasm in which underlying epigenetic alterations are only partially understood. Here, we analyze the reference epigenome of seven primary CLLs and the regulatory chromatin landscape of 107 primary cases in the context of normal B cell differentiation. We identify that the CLL chromatin landscape is largely influenced by distinct dynamics during normal B cell maturation. Beyond this, we define extensive catalogues of regulatory elements de novo reprogrammed in CLL as a whole and in its major clinico-biological subtypes classified by IGHV somatic hypermutation levels. We uncover that IGHV-unmutated CLLs harbor more active and open chromatin than IGHV-mutated cases. Furthermore, we show that de novo active regions in CLL are enriched for NFAT, FOX and TCF/LEF transcription factor family binding sites. Although most genetic alterations are not associated with consistent epigenetic profiles, CLLs with MYD88 mutations and trisomy 12 show distinct chromatin configurations. Furthermore, we observe that non-coding mutations in IGHV-mutated CLLs are enriched in H3K27ac-associated regulatory elements outside accessible chromatin. Overall, this study provides an integrative portrait of the CLL epigenome, identifies extensive networks of altered regulatory elements and sheds light on the relationship between the genetic and epigenetic architecture of the disease.
Autores: Zabaleta Lasarte, Nerea; Barberia, M.; Martin-Higueras, C. ; et al.

Título: CRISPR/Cas9-mediated glycolate oxidase disruption is an efficacious and safe treatment for primary hyperoxaluria type I

Revista: NATURE COMMUNICATIONS

ISSN: 2041-1723 Vol.9 2018 págs. 5454

Resumen

CRISPR/Cas9 technology offers novel approaches for the development of new therapies for many unmet clinical needs, including a significant number of inherited monogenic diseases. However, in vivo correction of disease-causing genes is still inefficient, especially for those diseases without selective advantage for corrected cells. We reasoned that substrate reduction therapies (SRT) targeting non-essential enzymes could provide an attractive alternative. Here we evaluate the therapeutic efficacy of an in vivo CRISPR/Cas9-mediated SRT to treat primary hyperoxaluria type I (PH1), a rare inborn dysfunction in glyoxylate metabolism that results in excessive hepatic oxalate production causing end-stage renal disease. A single systemic administration of an AAV8-CRISPR/Cas9 vector targeting glycolate oxidase, prevents oxalate overproduction and kidney damage, with no signs of toxicity in Agxt1(-/-) mice. Our results reveal that CRISPR/Cas9-mediated SRT represents a promising therapeutic option for PH1 that can be potentially applied to other metabolic diseases caused by the accumulation of toxic metabolites.
Autores: Garitano Trojaola, Andoni; San José Enériz, Edurne; Ezponda Itoiz, Teresa; et al.

Título: Deregulation of linc-PINT in acute lymphoblastic leukemia is implicated in abnormal proliferation of leukemic cells

Revista: ONCOTARGET

ISSN: 1949-2553 Vol.9 N° 16 2018 págs. 12842 - 12852

Resumen

Long Non-Coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides in length. Several lncRNAs are involved in cell proliferation and are deregulated in several human tumors. Few lncRNAs have been described to play a role in Acute Lymphoblastic Leukemia (ALL). In this study, we carried out a genome wide lncRNA expression profiling in ALL samples and peripheral blood samples obtained from healthy donors. We detected 43 lncRNAs that were aberrantly expressed in ALL. Interestingly, among them, linc-PINT showed a significant downregulation in T and B-ALL. Re-expression of linc-PINT in ALL cells induced inhibition of leukemic cell growth that was associated with apoptosis induction and cell cycle arrest in G2/M phase. linc-PINT induced the transcription of HMOX1 which reduced the viability of ALL cells. Intriguingly, we observed that treatment with anti-tumoral epigenetic drugs like LBH-589 (Panobinostat) and Curcumin induced the expression of linc-PINT and HMOX1 in ALL. These results indicate that the downregulation of linc-PINT plays a relevant role in the pathogenesis of ALL, and linc-PINT re-expression may be one of the mechanisms exerted by epigenetic drugs to reduce cell proliferation in ALL.
Autores: García Barchino, María José; Sarasquete, M. E.; Panizo Santos, Carlos Manuel; et al.

Título: Richter transformation driven by Epstein-Barr virus reactivation during therapy-related immunosuppression in chronic lymphocytic leukaemia

Revista: JOURNAL OF PATHOLOGY

ISSN: 0022-3417 Vol.245 N° 1 2018 págs. 61 - 73

Resumen

The increased risk of Richter transformation (RT) in patients with chronic lymphocytic leukaemia (CLL) due to Epstein-Barr virus (EBV) reactivation during immunosuppressive therapy with fludarabine other targeted agents remains controversial. Among 31 RT cases classified as diffuse large B-cell lymphoma (DLBCL), seven (23%) showed EBV expression. In contrast to EBV- tumours, EBV+ DLBCLs derived predominantly from IGVH-hypermutated CLL, and they also showed CLL-unrelated IGVH sequences more frequently. Intriguingly, despite having different cellular origins, clonally related and unrelated EBV+ DLBCLs shared a previous history of immunosuppressive chemo-immunotherapy, a non-germinal centre DLBCL phenotype, EBV latency programme type II or III, and very short survival. These data suggested that EBV reactivation during therapy-related immunosuppression can transform either CLL cells or non-tumoural B lymphocytes into EBV+ DLBCL. To investigate this hypothesis, xenogeneic transplantation of blood cells from 31 patients with CLL and monoclonal B-cell lymphocytosis (MBL) was performed in Rag2(-/-) IL2c(-/-) mice. Remarkably, the recipients' impaired immunosurveillance favoured the spontaneous outgrowth of EBV+ B-cell clones from 95% of CLL and 64% of MBL patients samples, but not from healthy donors. Eventually, these cells generated monoclonal tumours (mostly CLL-unrelated but also CLL-related), recapitulating the principal features of EBV+ DLBCL in patients. Accordingly, clonally related and unrelated EBV+ DLBCL xenografts showed indistinguishable cellular, virological and molecular features, and synergistically responded to combined inhibition of EBV replication with ganciclovir and B-cell receptor signalling with ibrutinib in vivo. Our study underscores the risk of RT driven by EBV in CLL patients receiving immunosuppressive therapies, and provides the scientific rationale for testing ganciclovir and ibrutinib in EBV+ DLBCL. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Autores: Wagener, R.; Schnaudt, C.; Kleinheinz, K.; et al.

Título: Large B-cell lymphomas with ALK-rearrangement display a different genetic and epigenetic profile than diffuse large B-cell lymphoma

Revista: BRITISH JOURNAL OF HAEMATOLOGY

ISSN: 0007-1048 Vol.182 2018 págs. 43 - 44
Autores: Caamano, M. L. A.; Lozano, J. J. G.; Ageda, C. A.; et al.

Título: Implante hematopoyético de una serie de pacientes movilizados con plerixafor. Estudio retrospectivo multicéntrico

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.103 N° Supl. 2 2018 págs. 244 - 244
Autores: Dupere-Richer, D.; Li, J. P. ; Maji, S. ; et al.

Título: Loss of KDM6A/UTX Accelerate the Development of Multiple Myeloma

Revista: BLOOD

ISSN: 0006-4971 Vol.132 N° Supl. 1 2018
Autores: Flinn, I. W. ; Montillo, M.; Nagy, Z.; et al.

Título: Characterization of the long-term efficacy and safety of Duvelisib monotherapy in patients with relapsed/refractory CLL/SLL on treatment for > 2 years across 4 clinical studies

Revista: BLOOD

ISSN: 0006-4971 Vol.132 N° Supl. 1 2018
Autores: Cuenca, I.; Sanchez-Vega, B. ; Paiva, Bruno; et al.

Título: Estudio del perfil genético en pacientes con amiloidosis de cadenas ligeras

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.103 N° Supl. 2 2018 págs. 91 - 91
Autores: Paiva, Bruno; Martinez-Cuadron, D.; Bergua-Burgues, J. M.; et al.

Título: Role of measurable residual disease (MRD) in redefining complete response (CR) in elderly patients with acute myeloid leukemia (AML): results from the Pethema-Flugaza phase III clinical trial

Revista: BLOOD

ISSN: 0006-4971 Vol.132 N° Supl. 1 2018 págs. 433
Autores: Alameda Serrano, Daniel; Vicari, M. ; Lara-Astiaso, D.; et al.

Título: Understanding the cellular origin and pathogenic transcriptional programs in Multiple Myeloma (MM) and Light-Chain Amyloidosis (AL) through the dissection of the normal Plasma Cell (PC) development

Revista: BLOOD

ISSN: 0006-4971 Vol.132 N° Supl. 1 2018 págs. 188
Autores: Puig, N.; Paiva, Bruno; Lasa Ventura, Marta; et al.

Título: Multidimensional immunophenotyping identifies hallmarks of systemic Light-chain Amyloidosis (AL) and maps the disease in the crossroad between MGUS and Multiple Myeloma (MM)

Revista: BLOOD

ISSN: 0006-4971 Vol.132 N° Supl. 1 2018
Autores: Abaigar, M. ; López Cadenas, F.; Ramos, F. ; et al.

Título: Perfil mutacional en pacientes diagnosticados de SMD de bajo riesgo sin sideroblastos en anillo

Revista: HAEMATOLOGICA

ISSN: 0390-6078 Vol.103 N° Supl. 2 2018 págs. 74 - 75
Autores: Ganan-Gomez, I.; Alfonso Piérola, Ana; Yang, H. ; et al.

Título: Cell-type specific mechanisms of hematopoietic stem cell (HSC) expansion underpin progressive disease in myelodysplastic syndromes (MDS) and provide a rationale for targeted therapies

Revista: BLOOD

ISSN: 0006-4971 Vol.132 N° Supl. 1 2018

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Autores: Feliu, J.; Panizo Santos, Carlos Manuel; Marcos Jubilar, María; et al.

Título: El laboratorio en las enfermedades hematológicas

Libro: La clínica y el laboratorio

2019 págs. 661 - 708
Autores: Ezponda Itoiz, Teresa; Alkorta Aranburu, Gorka; Prosper Cardoso, Felipe; et al.

Título: NGS data analysis process

Libro: Principles of Nutrigenetics and Nutrigenomics: Fundamentals of Individualized Nutrition

ISSN: 9780128045725; 9780128045879 2019 págs. 33 - 39

Resumen

The study of nutrigenetics and nutrigenomics requires an identification of the genetic background of an organism to determine how this affects nutrient metabolism and the effects that the nutrients have on it. Advances in sequencing technologies have caused a shift from gene-based to genome-wide analyses that have provided information previously unsuspected and unavailable. Although these techniques are commonly used, they are still evolving and susceptible to improvement: therefore, some potential biases need to be considered regarding their performance and use. In this chapter, we describe the most common techniques used to study nutrigenetics and nutrigenomics, focusing on key steps to be followed to obtain reliable results.

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Título: DeSarrollO de terapias CAR-T innovadoras para el trAtamiento de Tumores Hematológicos y Sólidos. (SOCRATHeS)

Código de expediente: 0011-1411-2022-000053

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2022 GN PROYECTOS ESTRATEGICOS DE I+D 2022-2025

Fecha de inicio: 01-05-2022

Fecha fin: 30-12-2024

Importe concedido: 371.489,00€

Otros fondos: -
Título: Bioingeniería avanzada para el desarrollo del tejido cardiaco y su aplicación al estudio y detección de cardiotoxicidad

Código de expediente: 0011-1411-2022-000071

Investigador principal: MANUEL MARIA MAZO VEGA.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2022 GN PROYECTOS ESTRATEGICOS DE I+D 2022-2025

Fecha de inicio: 03-04-2022

Fecha fin: 30-12-2024

Importe concedido: 196.436,13€

Otros fondos: -
Título: Terapias avanzadas

Código de expediente: RD21/0017/0009

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: INSTITUTO DE SALUD CARLOS III

Convocatoria: 2021 AES Redes de Investigación cooperativa orientadas a resultados (RICORS)

Fecha de inicio: 01-01-2022

Fecha fin: 31-12-2024

Importe concedido: 86.316,00€

Otros fondos: Fondos FEDER
Título: CARDIOPRINT_Biofabricación avanzada multifunción en 3D para la generación de tejido cardíaco terapéuti co a escala humana diseñado por ordenador.

Código de expediente: PLEC2021-008127

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: AGENCIA ESTATAL DE INVESTIGACION

Convocatoria: 2021 AEI Proyectos de I+D+i en líneas estratégicas

Fecha de inicio: 01-12-2021

Fecha fin: 31-12-2024

Importe concedido: 203.867,00€

Otros fondos: -
Título: Bioingenieria personalizada para el tratamiento de las enfermedades cardiovasculares. Estudio de la implicación del género

Código de expediente: 0011-1383-2022-000015(PC020-21-022 BIOGEN)

Investigador principal: MANUEL MARIA MAZO VEGA.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2022 GN Proyectos Colaborativos

Fecha de inicio: 01-12-2021

Fecha fin: 30-11-2024

Importe concedido: 211.870,50€

Otros fondos: -
Título: New targets and designs to improve CAR-T cell based immunotherapy against pancreatic cancer (CarPanTu)

Código de expediente: PLEC2021-008094

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: AGENCIA ESTATAL DE INVESTIGACION

Convocatoria: 2021 AEI Proyectos de I+D+i en líneas estratégicas

Fecha de inicio: 01-11-2021

Fecha fin: 31-10-2024

Importe concedido: 100.042,00€

Otros fondos: Fondos MRR
Título: Biotecnología aplicada a la obtención de polímeros imprimibles para aplicaciones biomédicas a partir de subproductos de origen agroalimentario de Navarra (IMPRIMED)

Código de expediente: 0011-1411-2021-000096

Investigador principal: MANUEL MARIA MAZO VEGA.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2021 GN PROYECTOS ESTRATEGICOS DE I+D 2021-2024

Fecha de inicio: 01-06-2021

Fecha fin: 31-12-2023

Importe concedido: 223.280,88€

Otros fondos: -
Título: Aplicaciones del estudio multi-ómico de la microbiota al desarrollo de soluciones biotecnológicas innovadoras en el área de la salud (microBiomics)

Código de expediente: 0011-1411-2021-000106

Investigador principal: MARIA TERESA HERRAIZ BAYOD.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2021 GN PROYECTOS ESTRATEGICOS DE I+D 2021-2024

Fecha de inicio: 15-04-2021

Fecha fin: 30-11-2023

Importe concedido: 366.577,17€

Otros fondos: -
Título: Papel de los mecanimso de regulación trascripcional en la patogenia y el tratamiento de los SMD

Código de expediente: PI20/01308

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: INSTITUTO DE SALUD CARLOS III

Convocatoria: 2020 AES Proyectos de investigación

Fecha de inicio: 01-01-2021

Fecha fin: 31-12-2023

Importe concedido: 275.880,00€

Otros fondos: Fondos FEDER
Título: Alianza en Genómica Avanzada para el desarrollo de Terapias Personalizadas en Navarra

Código de expediente: 0011-1411-2020-000010

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: FIMA 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022

Fecha de inicio: 17-06-2020

Fecha fin: 30-11-2022

Importe concedido: 725.480,08€

Otros fondos: -
Título: Alianza en Genómica Avanzada para el desarrollo de Terapias Avanzadas en Navarra (AGATA)

Código de expediente: 0011-1411-2020-000011

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2020 GN PROYECTOS ESTRATEGICOS DE I+D 2020-2022

Fecha de inicio: 16-06-2020

Fecha fin: 30-11-2022

Importe concedido: 441.998,75€

Otros fondos: -
Título: Transcriptional and gene regulatory networks in acute myeloid leukemia secondary to myelodysplastic syndromes: identification of novel therapeutic targets

Código de expediente: 0011-0537-2019-000001

Investigador principal: NEREA BERASTEGUI ZUFIAURRE.

Financiador: GOBIERNO DE NAVARRA / DPTO. EDUCACIÓN CULTURA Y TURISMO

Convocatoria: FIMA GNE 2019 BECAS PREDOCTORALES

Fecha de inicio: 01-06-2020

Fecha fin: 01-10-2023

Importe concedido: 68.715,96€

Otros fondos: -
Título: Metabolic vulnerabilities for personalized therapeutic approaches in acute myeloid leukemia

Código de expediente: 0011-2750-2019-000001

Investigador principal: FELIPE LUIS PROSPER CARDOSO, FRANCISCO JAVIER PLANES PEDREÑO.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2019 GN PERMED

Fecha de inicio: 01-03-2020

Fecha fin: 28-02-2023

Importe concedido: 228.600,00€

Otros fondos: -
Título: Desarrollo y evaluación de inmunoterapia celular mediante CART alogénicas para el tratamiento de la Leucemia Mieloide Aguda

Código de expediente: 0011-1383-2020-000010 PC011

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2020 GN Proyectos Colaborativos

Fecha de inicio: 01-12-2019

Fecha fin: 30-11-2022

Importe concedido: 180.675,00€

Otros fondos: -
Título: Caracterización bioinformática, del perfil transcriptómico y epigenético de células madre hematopoyéticas (CD34+). Integración de ambas tecnologías genómicas para identificar "gene regulatory networks"

Código de expediente:

Investigador principal: MARINA AINCIBURU FERNANDEZ.

Financiador: GOBIERNO DE NAVARRA / DPTO. EDUCACIÓN CULTURA Y TURISMO

Convocatoria: GNE 2018 BECAS PREDOCTORALES

Fecha de inicio: 01-04-2019

Fecha fin: 08-09-2019

Importe concedido: 68.718,00€

Otros fondos: Fondos FEDER
Título: Desarrollo EStratégico de terapias CART para el tratamiento de Tumores Hematológicos y Sólidos (DESCARTHeS)

Código de expediente: 0011-1411-2019-000072

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2019 GN PROYECTOS ESTRATEGICOS DE I+D 2019-2021

Fecha de inicio: 01-04-2019

Fecha fin: 30-11-2021

Importe concedido: 164.695,50€

Otros fondos: -
Título: Optimización de nuevos agentes epigenéticos para el tratamiento de la Leucemia Mieloide Aguda.

Código de expediente: 0011-1383-2019-000006

Investigador principal: MARIA OBDULIA RABAL GRACIA.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2019 - GN INDUSTRIA PROYECTOS CENTROS TECNOLOGICOS Y ORGANISMOS DE INVESTIGACION

Fecha de inicio: 01-12-2018

Fecha fin: 30-11-2019

Importe concedido: 125.835,30€

Otros fondos: -
Título: Terapia basada en RNA mediante quimeras aptámero-siRNAs contra lncRNAs en el mieloma múltiple. RTHALMY

Código de expediente: SAF2017-92632-EXP

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN

Convocatoria: 2017 - PROYECTOS EXPLORA CIENCIA Y EXPLORA TECNOLOGIA

Fecha de inicio: 01-11-2018

Fecha fin: 31-12-2020

Importe concedido: 84.700,00€

Otros fondos: Fondos FEDER
Título: Identificación y estudio funcional de transcritos quiméricos no codificantes en el mieloma múltiple

Código de expediente: FPU17/02733

Investigador principal: ANE AMUNDARAIN IRAOLA.

Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN

Convocatoria: 2017 - MINECO BECAS FPU 2017 - MINECO BECAS FPU 2017 - MINECO BECAS FPU

Fecha de inicio: 01-10-2018

Fecha fin: 28-02-2023

Importe concedido: 91.828,32€

Otros fondos: Fondos FEDER
Título: Contratación Río Hortega

Código de expediente: CM17/00046

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: INSTITUTO DE SALUD CARLOS III

Convocatoria: AES 2017 RIO HORTEGA

Fecha de inicio: 13-04-2018

Fecha fin: 12-04-2020

Importe concedido: 56.732,00€

Otros fondos: -
Título: MINERVA. Estudio genómico para la personalización del diagnóstico y el tratamiento de los pacientes con insuficiencia Cardíaca crónica y enfermedad renal crónica (Medicina cardIoreNal pERsonalizada en NaVArra)

Código de expediente: 0011-1411-2018-000043

Investigador principal: DOMINGO FRANCISCO JAVIER DIEZ MARTINEZ, DOMINGO FRANCISCO JAVIER DIEZ MARTINEZ.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2018- GN PROY. ESTRATEGICOS DE I+D 2018-2020

Fecha de inicio: 01-04-2018

Fecha fin: 30-11-2020

Importe concedido: 1.001.241,69€

Otros fondos: -
Título: GENEURONA. Implantación del diagnóstico genómico de la epilepsia y la migraña en Navarra

Código de expediente: 0011-1411-2018-000044

Investigador principal: ANA MARIA GARCIA OSTA.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2018- GN PROY. ESTRATEGICOS DE I+D 2018-2020

Fecha de inicio: 01-04-2018

Fecha fin: 30-11-2020

Importe concedido: 476.239,53€

Otros fondos: -
Título: Estudio genómico para la personalización del diagnóstico y el tratamiento de los pacientes con insuficiencia cardiaca crónica y enfermedad renal crónica (Medicina cardIoreNal pERsonalizada en NaVArra) (MINERVA)

Código de expediente: 0011-1411-2018-000036

Investigador principal: JUAN JOSE GAVIRA GOMEZ.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2018 GN PROYECTOS ESTRATEGICOS DE I+D 2018-2020

Fecha de inicio: 01-04-2018

Fecha fin: 30-11-2020

Importe concedido: 97.237,60€

Otros fondos: -
Título: Detección y validación funcional del trasncriptoma completo y análisis de genes esenciales y sintéticos letales en el Mieloma Múltiple

Código de expediente: FI17/00297

Investigador principal: LUIS VITORES VALCARCEL GARCIA.

Financiador: INSTITUTO DE SALUD CARLOS III

Convocatoria: 2017 AYUDAS PREDOCTORALES DE FORMACION EN INVESTIGACION EN SALUD PFIS

Fecha de inicio: 24-01-2018

Fecha fin: 23-01-2022

Importe concedido: 82.400,00€

Otros fondos: -
Título: Estudio de la arquitectura genómica y transcripcional en SMDs como herramienta para la determinación de factores pronósticos y nuevas dianas terapeúticas.

Código de expediente: PI17/00701

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: INSTITUTO DE SALUD CARLOS III

Convocatoria: AES2017 PROYECTOS DE INVESTIGACIÓN

Fecha de inicio: 01-01-2018

Fecha fin: 31-12-2020

Importe concedido: 209.330,00€

Otros fondos: Fondos FEDER
Título: Plataformas automáticas de producción de células CAR T para el tratamiento de leucemia B y linfoma B

Código de expediente: RTC-2017-6578-1

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN

Convocatoria: 2017 MINECO RETOS COLABORACIÓN

Fecha de inicio: 01-01-2018

Fecha fin: 31-10-2021

Importe concedido: 100.985,84€

Otros fondos: Fondos FEDER
Título: Ayuda del ISCIII Sara Borrell

Código de expediente: CD17/00108

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: INSTITUTO DE SALUD CARLOS III

Convocatoria: AES2017 SARA BORRELL

Fecha de inicio: 01-01-2018

Fecha fin: 31-12-2020

Importe concedido: 80.598,00€

Otros fondos: -
Título: Tecnología de secuenciación de nueva generación (NGS) para optimizar la eficacia del diagnóstico y tratamiento en pacientes con tumores de alta mortalidad (DIANA: Diagnostico biomédico e Innovación Abierta en Navarra)

Código de expediente: 0011-1411-2017-000028

Investigador principal: MARIA JOSE CALASANZ ABINZANO.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2017 GN ESTRATEGICOS

Fecha de inicio: 01-04-2017

Fecha fin: 30-11-2019

Importe concedido: 821.776,08€

Otros fondos: -
Título: Tecnología de secuenciación de nueva generación (NGS) para optimizar la eficacia del diagnóstico y tratamiento en pacientes con tumores de alta mortalidad (DIANA: Diagnostico biomédico e Innovación Abierta en Navarra)

Código de expediente: 0011-1411-2017-000030

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: GOBIERNO DE NAVARRA

Convocatoria: 2017 GN ESTRATEGICOS

Fecha de inicio: 01-04-2017

Fecha fin: 30-11-2019

Importe concedido: 37.315,72€

Otros fondos: -
Título: Detección y validación funcional de los RNAs largos no codificantes específicos de la célula plasmática en el Mieloma Múltiple

Código de expediente: PI16/02024

Investigador principal: XABIER AGUIRRE ENA.

Financiador: INSTITUTO DE SALUD CARLOS III

Convocatoria: 2016 - PROYECTOS DE I+D EN SALUD

Fecha de inicio: 01-01-2017

Fecha fin: 31-12-2019

Importe concedido: 98.615,00€

Otros fondos: Fondos FEDER
Título: Inhibición de la actividad metiltransferasa de G9a mediante moléculas pequeñas como estrategia terapéutica en tumores hematológicos.

Código de expediente: FI16/00275

Investigador principal: ARANTXA CARRASCO LEON.

Financiador: INSTITUTO DE SALUD CARLOS III

Convocatoria: 2016 AYUDAS PREDOCTORALES DE FORMACION EN INVESTIGACION EN SALUD PFIS

Fecha de inicio: 01-01-2017

Fecha fin: 31-12-2020

Importe concedido: 82.400,00€

Otros fondos: Fondos FEDER
Título: Identificación de nuevas alteraciones en síndrome mielodisplásico en riesgo de progresión a leucemia mieloide aguda: biomarcadores y nuevas dianas terapéuticas mediante NGS

Código de expediente: PI16/00159

Investigador principal: MARTA FERNANDEZ MERCADO, MARIA JOSE CALASANZ ABINZANO.

Financiador: INSTITUTO DE SALUD CARLOS III

Convocatoria: AES2017 PROYECTOS DE INVESTIGACIÓN

Fecha de inicio: 01-01-2017

Fecha fin: 30-06-2020

Importe concedido: 122.815,00€

Otros fondos: Fondos FEDER
Título: Detección, anotación y análisis del papel de los eRNAs en el Mieloma Múltiple

Código de expediente: 40_2016

Investigador principal: XABIER AGUIRRE ENA.

Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD

Convocatoria: 2016 PROYECTOS DE I+D EN SALUD

Fecha de inicio: 09-12-2016

Fecha fin: 08-12-2019

Importe concedido: 63.549,00€

Otros fondos: Fondos FEDER
Título: Nanopartículas de esqualeno-adenosina para el tratamiento de la isquemia-reperfusión cardiaca

Código de expediente: PCIN-2016-046

Investigador principal: MARIA JOSE BLANCO PRIETO.

Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN

Convocatoria: 2016 MINECO ACCIONES DE PROGRAMACIÓN CONJUNTA INTERNACIONAL

Fecha de inicio: 01-05-2016

Fecha fin: 31-12-2020

Importe concedido: 98.000,00€

Otros fondos: -
Título: Understanding primary hyperoxaluria type 1 towards the development of innovative therapeutic strategies (ERARE)

Código de expediente: AC15/00036

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: INSTITUTO DE SALUD CARLOS III

Convocatoria: 2015 AES ACCIONES COMPLEMENTARIAS

Fecha de inicio: 01-01-2016

Fecha fin: 31-12-2019

Importe concedido: 99.946,00€

Otros fondos: -
Título: Inhibición de la actividad metiltransferasa de G9a mediante moléculas pequeñas como estrategia terapéutica en tumores hematológicos

Código de expediente: PI14/01867

Investigador principal: FELIPE LUIS PROSPER CARDOSO.

Financiador: INSTITUTO DE SALUD CARLOS III

Convocatoria: 2014 - PROYECTOS DE I+D EN SALUD

Fecha de inicio: 01-01-2015

Fecha fin: 30-06-2018

Importe concedido: 207.515,00€

Otros fondos: Fondos FEDER

Título: SyLeNCe: Synapses between Leukaemia and its Neighbouring Cells

Código de expediente: 837491

Investigador principal: ISABEL CALVO ARNEDO

Financiador: COMISIÓN EUROPEA

Convocatoria: H2020-EC-MSCA-IF

Fecha de inicio: 01-07-2020

Fecha fin: 30-06-2022

Importe concedido: 160.932,48€

Otros fondos: -
Título: Elucidating transcriptional rewiring on hematological malignancies via computational methods

Código de expediente: 898356

Investigador principal: MIKEL HERNAEZ ARRAZOLA

Financiador: COMISIÓN EUROPEA

Convocatoria: H2020-EC-MSCA-IF

Fecha de inicio: 01-03-2020

Fecha fin: 28-02-2022

Importe concedido: 172.932,48€

Otros fondos: -
Título: EPICA: Dual epigenetic targeting and immunotherapy to fight against cancer.

Código de expediente: AC16/00041

Investigador principal: FELIPE LUIS PROSPER CARDOSO

Financiador: INSTITUTO DE SALUD CARLOS III

Convocatoria: TRANSCAN-2

Fecha de inicio: 01-03-2017

Fecha fin: 31-08-2020

Importe concedido: 144.159,40€

Otros fondos: Fondos FEDER
Título: DECAL

Código de expediente:

Investigador principal: TERESA EZPONDA ITOIZ

Financiador: GILEAD SCIENCES, S.L.

Convocatoria: GILEAD 2015

Fecha de inicio: 24-06-2016

Fecha fin: 23-06-2018

Importe concedido: 115.000,00€

Otros fondos: -

Título: Identification of the epigenomic and transcriptomic alterations in the transformation of benign monoclonal gammapathies to symptomatic multiple myeloma.

Investigador principal: FELIPE LUIS PROSPER CARDOSO

Financiador: FUNDACION BBVA

Convocatoria: 2021 Fundación BBVA Proyectos de investigación

Fecha de inicio: 01-07-2022

Fecha fin: 30-06-2024

Importe concedido: 149.984,50€
Título: Gene Regulatory NETworks in NORmal and MALignant Hematopoiesis- Identification and Targeting (GR-NET NORMAL-HIT

Investigador principal: FELIPE LUIS PROSPER CARDOSO

Financiador: FUNDACIÓN BANCARIA LA CAIXA

Convocatoria: 2020 FD La Caixa Health Research

Fecha de inicio: 01-12-2020

Fecha fin: 30-11-2023

Importe concedido: 411.250,00€
Título: Deciphering the role of transcription factors as chromatin modulators and drivers of lymphoid neoplasm

Investigador principal: XABIER AGUIRRE ENA

Financiador: FUNDACIO "LA MARATO DE TV3"

Convocatoria: FIMA 2019 FD LA MARATÓ TV3 PROYECTOS DE INVESTIGACIÓN

Fecha de inicio: 30-07-2020

Fecha fin: 29-07-2023

Importe concedido: 101.875,00€
Título: Caracterización del transcriptoma y vías reguladoras génicas en el eje envejecimiento-hematopoyesis clonal-síndromes mielodisplásicos como herramienta para la identificación de nuevas dianas terapéuticas

Investigador principal: TERESA EZPONDA ITOIZ

Financiador: ASOCIACION ESPAÑOLA CONTRA EL CANCER

Convocatoria: 2019 AECC Investigador, 2019 AECC Investigador

Fecha de inicio: 01-12-2019

Fecha fin: 30-11-2023

Importe concedido: 200.000,00€
Título: A systems biology approach to reveal the niche composition and connectivity in aging and malignant transformation at the single cell level

Investigador principal: ITZIAR CENZANO ARMENDARIZ

Financiador: ASOCIACION ESPAÑOLA CONTRA EL CANCER

Convocatoria: FIMA 2019 Predoctorales AECC, FIMA 2019 Predoctorales AECC

Fecha de inicio: 01-12-2019

Fecha fin: 30-11-2023

Importe concedido: 91.530,54€
Título: SUBCONTRACTING RNA SEQ

Investigador principal: FELIPE LUIS PROSPER CARDOSO

Fecha de inicio: 20-06-2019

Fecha fin: 20-06-2020

Importe: 0

Otros fondos: -
Título: GENOMICS OF 5q- SYNDROME AND INMUNE RESIST TO REVLIMID

Investigador principal: FELIPE LUIS PROSPER CARDOSO

Fecha de inicio: 13-05-2019

Fecha fin: 30-09-2021

Importe: 0

Otros fondos: -
Título: Development of non-genotoxic conditioning regimens for hematopoietic stem cell transplantation in Ataxia Telangiectasia.

Investigador principal: FELIPE LUIS PROSPER CARDOSO

Financiador: Asocición Española Familia Ataxia Telangiectasia

Convocatoria: 2017 AEFAT

Fecha de inicio: 24-04-2018

Fecha fin: 24-04-2021

Importe concedido: 150.000,00€
Título: Investigación y explotación de la función de microRNAs aberrantemente expresados en linfomas B difusos de células grandes

Investigador principal: FELIPE LUIS PROSPER CARDOSO

Financiador: ASOCIACION ESPAÑOLA CONTRA EL CANCER

Convocatoria: 2017 AECC Postdoctorales

Fecha de inicio: 01-05-2017

Fecha fin: 31-07-2019

Importe concedido: 56.250,00€
Título: Analysis of functional role of the IncRNAs in multiple myeloma

Investigador principal: FELIPE LUIS PROSPER CARDOSO

Financiador: GILEAD SCIENCES, S.L.

Convocatoria: 2016 GILEAD

Fecha de inicio: 20-01-2017

Fecha fin: 20-01-2019

Importe concedido: 49.967,79€

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