Grupos Investigadores

Miembros del Grupo

Líneas de Investigación

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

Palabras Clave

  • Síndrome mielodisplásico
  • Nicho hematopoyético
  • Mieloma Múltiple
  • Metilación
  • Metabolismo
  • Leucemia
  • Histonas
  • Epigenómica

Publicaciones Científicas desde 2018

  • Autores: Amundarain, A.; Valcárcel, L. V.; Ordóñez Ciriza, Raquel; et al.
    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.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.36 N° 2 2022 págs. 583 - 587
  • Autores: McLornan, D. P. (Autor de correspondencia); Gras, L.; Martin, I.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN 0007-1048 Vol.198 N° 1 2022 págs. 209 - 213
  • Autores: Moreira-Silva, F.; Outeiro-Pinho, G.; Lobo, J.; et al.
    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: DePasquale, E. A. K.; Ssozi, D.; Ainciburu Fernandez, Marina; et al.
    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: Martínez Turrillas, Rebeca; Martin Mallo, Angel; Rodríguez Díaz, Saray; et al.
    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: Viñado, A. C.; Calvo Arnedo, Isabel; Cenzano Armendariz, Itziar; et al.
    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: Saumell, S.; Fernández-Serrano, M.; Mesa, A.; et al.
    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: Peng, J.; SERRANO SANZ, Guillermo; Traniello, I. M.; et al.
    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: Zapata-Linares, N.; Toillon, I.; Wanherdrick, K.; et al.
    Revista: OSTEOARTHRITIS AND CARTILAGE
    ISSN 1063-4584 Vol.30 N° Supl. 1 2022 págs. S303
  • Autores: Carrasco Leon, Arantxa; Amundarain, A.; Gomez Echarte, Nahia; et al.
    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: Maes, K. (Autor de correspondencia); Mondino, A.; Lasarte Sagastibelza, Juan José; et al.
    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: Palacios-Berraquero, M. L.; Alfonso Piérola, Ana (Autor de correspondencia)
    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: Polverelli, N. (Autor de correspondencia); Mauff, K.; Kroger, N.; et al.
    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: Zawislak, A. (Autor de correspondencia); Wozniak, K.; Aguirre Ena, Xabier; et al.
    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: Steensma, D. P.; Wermke, M.; Klimek, V. M.; et al.
    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: Chari, A. (Autor de correspondencia); Rodríguez Otero, Paula; McCarthy, H. ; et al.
    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: Garcia-Gomez, A. (Autor de correspondencia); Li, T.; de la Calle-Fabregat, C.; et al.
    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: Vilarrasa-Blasi, R.; Soler-Vila, P.; Verdaguer-Dot, N.; et al.
    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: Parra-Salinas, I. (Autor de correspondencia); Bermudez, A.; Lopez-Corral, L.; et al.
    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: Cordero, O. J. (Autor de correspondencia); Rafael-Vidal, C.; Varela-Calvino, R.; et al.
    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.
    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: Carrasco Leon, Arantxa; Ezponda Itoiz, Teresa; Meydan, C.; et al.
    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: Antelo, M. L. (Autor de correspondencia); Altuna, A.; Gimeno, J. J.; et al.
    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: Isidro, I. A. (Autor de correspondencia); Vicente, P.; Pais, D. A. M.; et al.
    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: Rabal Gracia, María Obdulia; San José Enériz, Edurne; Aguirre Ena, Xabier; et al.
    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: Cuenca, I. ; Alameda Serrano, Daniel; Sánchez, B.; et al.
    Revista: LEUKEMIA
    ISSN 0887-6924 Vol.35 N° 1 2021 págs. 245 - 249
  • Autores: Valcárcel, L. V.; Amundarain, A.; Kulis, M.; et al.
    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: Perez-Amill, L.; Suñe, G.; Antoñana-Vildosola, A.; et al.
    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: Haertle, L.; Barrio, S.; Munawar, U.; et al.
    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: Sargas, C.; Ayala, R.; Chillón, M. C.; et al.
    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: Dhillon, P.; Park, J. (Autor de correspondencia); del-Pozo, C. H.; et al.
    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: Jagannath, S. (Autor de correspondencia); Lin, Y.; Goldschmidt, H.; et al.
    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: Català-Moll, F.; Ferreté-Bonastre, A. G.; Li, T. L.; et al.
    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: Grigorian-Shamagian, L.; Sanz-Ruiz, R.; Climent, A.; et al.
    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.
    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: Jiménez Solas, T.; Muntion Olave, S.; López, F.; et al.
    Revista: LEUKEMIA RESEARCH
    ISSN 0145-2126 Vol.108 2021 págs. S39 - S39
  • Autores: Ainciburu Fernandez, Marina; Ezponda Itoiz, Teresa; Berastegui Zufiaurre, Nerea; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 119 - 119
  • Autores: Rodríguez Márquez, Paula; Calleja Cervantes, María Erendira; SERRANO SANZ, Guillermo; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 58 - 59
  • Autores: Calvo Arnedo, Isabel; Cenzano Armendariz, Itziar; Ye, J.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 119 - 120
  • Autores: Molero, A.; Tazón-Vega, B.; Gallur, L.; et al.
    Revista: LEUKEMIA RESEARCH
    ISSN 0145-2126 Vol.108 2021 págs. S34 - S35
  • Autores: Gimenez Camino, Naroa; San José Enériz, Edurne; Miranda, E.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 89 - 90
  • Autores: López Cadenas, F.; Badiella Busquets, L.; Bernal Castillo, T.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 244 - 245
  • Autores: Martin Mallo, Angel; Palacios Berraquero, María Luisa; San Martín Úriz, Patxi; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 70 - 70
  • Autores: Villar Fernández, Sara; Ariceta, B.; Agirre, X.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 86 - 87
  • Autores: Calviño Sampedro, Cristina; Ceballos, C.; Inoges Sancho, Susana Inmaculada; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 59 - 59
  • Autores: Vítores Valcárcel, L.; Amundarain, A. ; Kulis, M.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 68 - 69
  • Autores: Oriol, A.; Manier, S.; Kansagra, A.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 78 - 79
  • Autores: Wong, L.; Lamba, M.; Núñez, M. D. J.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN 0007-1048 Vol.193 N° Supl. 1 2021 págs. 152 - 153
  • Autores: Berastegui Zufiaurre, Nerea; Ainciburu Fernandez, Marina; Alfonso Piérola, Ana; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 99 - 100
  • Autores: Palacios Berraquero, María Luisa; Berastegui Zufiaurre, Nerea; Burgos Rodríguez, Leire; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 260 - 260
  • Autores: Molero, A.; Gallur, L.; Tatón-Vega, B.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 241 - 242
  • Autores: Molero, A.; Gallur, L.; Tazón-Vega, B.; et al.
    Revista: LEUKEMIA RESEARCH
    ISSN 0145-2126 Vol.108 2021 págs. S35 - S36
  • Autores: Viñado, A. C.; Calvo Arnedo, Isabel; Cenzano Armendariz, Itziar; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 82 - 82
  • Autores: Molero, A.; Tazón-Vega, B.; Gallur, L.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 240 - 241
  • Autores: Barrena Acuña, N.; Vitores Valcárcel, L.; Olaverri Mendizabal, L.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 68 - 68
  • Autores: Bailén-Almorox, R.; Pascual-Cascón, M. J.; Guerreiro, M.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 2021 págs. 37 - 38
  • Autores: Viñado, A. C.; Calvo Arnedo, Isabel; Cenzano Armendariz, Itziar (Autor de correspondencia); et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 42 - 43
  • Autores: Parra Salinas, I. M.; Bermúdez Rodríguez, A.; López Corral, L.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 275 - 276
  • Autores: Tamariz Amador, Luis Esteban; Rodríguez Otero, Paula; Jiménez de Ubieto, A.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.106 N° 10 s2 2021 págs. 64 - 65
  • Autores: Sánchez-Guijo, F. ; García-Olmo, D.; Prosper Cardoso, Felipe; et al.
    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: Galluzzi, L. (Autor de correspondencia); Vitale, I.; Warren, S.; et al.
    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: Rodríguez Otero, Paula; Reis de Carvalho, Joana Sofía; Alfonso Piérola, Ana; et al.
    Revista: JCO GLOBAL ONCOLOGY
    ISSN 2687-8941 Vol.6 2020 págs. 904 - 905
  • Autores: Soria-Juan, B.; Escacena, N. ; Capilla-Gonzalez, V.; et al.
    Revista: FRONTIERS IN IMMUNOLOGY
    ISSN 1664-3224 Vol.11 2020
  • Autores: Ruiz Villalba, Adrián; Romero, JP. ; Hernández Velasco, Silvia Clara; et al.
    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: Duran-Ferrer, M. (Autor de correspondencia); Clot, G.; Nadeu, F.; et al.
    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: Yusuf, R. Z.; Sáez Ochoa, Borja; Sharda, A.; et al.
    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: Sánchez-Herrero, A.; Calvo, I. A. ; Flandes Iparraguirre, María; et al.
    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.
    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: Aguirre, P.; Ariceta, B.; Viguria, M. C.; et al.
    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: Garcés Latre, Juan José; Simicek, M.; Vicari, M.; et al.
    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: Sanchez-Guijo, F.; Garcia-Arranz, M.; Lopez-Parra, M.; et al.
    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: Saenz-Pipaon, G.; San Martín Úriz, Patxi; Planell, N.; et al.
    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: Aguilera Díaz, Almudena; Vázquez Urio, Iria; Ariceta, B.; et al.
    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: Palomo, L.; Ibáñez, M.; Abáigar, M.; et al.
    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: Chatonnet, F. ; Pignarre, A.; Serandour, A. A.; et al.
    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: Monteil, V.; Kwon, H.; Prado, P.; et al.
    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: Aguilera-Diaz, A.; Larráyoz Ilundáin, María José; Palomino-Echeverria, S.; et al.
    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: Ordóñez Ciriza, Raquel; Kulis, M.; Russiñol, N.; et al.
    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: Heilig, C. E.; Badoglio, M.; Labopin, M.; et al.
    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: Richardson, P. G.; Vangsted, A. J.; Ramasamy, K.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 2020
  • Autores: Weisel, K.; Rodríguez Otero, Paula; Davies, F. ; et al.
    Revista: ONCOLOGY RESEARCH AND TREATMENT
    ISSN 2296-5270 Vol.43 N° SUPPL 4 2020 págs. 118 - 118
  • Autores: Kwon, M. ; Bailen, R. ; Cascon, M. J. P. ; et al.
    Revista: BONE MARROW TRANSPLANTATION
    ISSN 0268-3369 Vol.55 N° SUPPL 1 2020 págs. 342 - 343
  • Autores: Dybko, J. ; Wendel, L. ; Knelange, N. ; et al.
    Revista: BONE MARROW TRANSPLANTATION
    ISSN 0268-3369 Vol.55 N° SUPPL 1 2020 págs. 472 - 473
  • Autores: Ordóñez Ciriza, Raquel; Martínez Calle, Nicolás; Aguirre Ena, Xabier (Autor de correspondencia); et al.
    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)
    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.
    Revista: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
    ISSN 1079-5642 Vol.39 N° 3 2019 págs. E106 - E106
  • Autores: Redondo, A. M.; Valcarce, D. ; Gonzalez-Rodriguez, A. P. ; et al.
    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.
    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: Moreno Narro, Laura; Pérez Ruiz, Cristina; Zabaleta Azpiroz, Aintzane; et al.
    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: Naqvi, K.; Sasaki, K.; Montalban-Bravo, G.; et al.
    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.
    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: Martínez Calle, Nicolás; Pascual, M.; Ordóñez Ciriza, Raquel; et al.
    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: Paya-Milans, M.; Poza-Viejo, L.; San Martín Úriz, Patxi; et al.
    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: Aguirre Ena, Xabier (Autor de correspondencia); Meydan, C.; Jiang, Y. W.; et al.
    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: San José Enériz, Edurne; Gimenez Camino, Naroa; Aguirre Ena, Xabier; et al.
    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: Puig, N. ; Paiva, Bruno (Autor de correspondencia); Lasa Ventura, Marta; et al.
    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: Carazo Melo, Fernando; San José Enériz, Edurne; Garate Iturriagagoitia, Leire; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.134 N° supl.1 2019
  • Autores: Carrasco Leon, Arantxa; Ezponda Itoiz, Teresa; Meydan, C.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 2019 págs. 11 - 11
  • Autores: Carrasco-Leon, A. ; Ezponda Itoiz, Teresa; Meydan, C. ; et al.
    Revista: CLINICAL LYMPHOMA MYELOMA AND LEUKEMIA
    ISSN 2152-2650 Vol.19 N° 10 2019 págs. E354 - E355
  • Autores: Riego Repullo, Victoria; Blasco-Iturri, Z. ; Villar Fernández, Sara; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 N° S3 2019 págs. 110 - 111
  • Autores: Sargas, C.; Ayala, R. ; Chillon, C. ; et al.
    Revista: ANNALS OF HEMATOLOGY
    ISSN 0939-5555 Vol.98 N° Suppl. 1 2019 págs. S38 - S39
  • Autores: San José Enériz, Edurne; Gimenez-Camino, N.; Rabal, O. ; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 2019 págs. 242 - 242
  • Autores: Ariceta-Ganuza, B.; Mañú Arruti, Amagoia; Larráyoz Ilundáin, María José; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 N° S3 2019 págs. 249 - 249
  • Autores: Prieto-Conde, M. I. ; Vázquez Urio, Iria; Fernández Mercado, Marta; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 N° S3 2019 págs. 266 - 266
  • Autores: Aguilera Díaz, Almudena; Vázquez Urio, Iria; Ariceta, B.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 N° S3 2019 págs. 110 - 110
  • Autores: Colyn, L.; Alvarez-Sola, G.; Latasa Sada, María Ujué; et al.
    Revista: JOURNAL OF HEPATOLOGY (ONLINE)
    ISSN 0168-8278 Vol.70 N° Supl. 1 2019 págs. E27 - E28
  • Autores: Alameda Serrano, Daniel; Puig, N. ; Cedena, M. T. ; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 2019 págs. 12 - 12
  • Autores: Ariceta-Ganuza, B.; Aguilera Díaz, Almudena; Vázquez Urio, Iria; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 N° S3 2019 págs. 174 - 174
  • Autores: Aguilera Díaz, Almudena; Palomino-Echeverria, S.; Vázquez Urio, Iria; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 N° S3 2019 págs. 72 - 73
  • Autores: Pena Carbó, Esther; Munoz, R. G.; López Díaz de Cerio, Ascensión; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 2019 págs. 3 - 4
  • Autores: Ordóñez Ciriza, Raquel; Kulis, M. ; Russinol, N. ; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 N° S3 2019 págs. 19 - 20
  • Autores: Carazo Melo, Fernando; San José Enériz, Edurne; Garate, L.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 2019 págs. 49 - 49
  • Autores: Ezponda Itoiz, Teresa; Romero Riojas, Juan Pablo; Ainciburu Fernandez, Marina; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 2019 págs. 88 - 88
  • Autores: Aguirre-Ruiz, P. ; Viguria, M. C.; Blasco-Iturri, Z. ; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 N° S3 2019 págs. 329 - 330
  • Autores: Vinado-Solanas, A. C. ; Calvo Arnedo, Isabel; Cenzano Armendariz, Itziar; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 2019 págs. 2 - 2
  • Autores: Blasco-Iturri, Z.; Vázquez Urio, Iria; Ariceta, B.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.104 N° S3 2019 págs. 56 - 57
  • Autores: San José Enériz, Edurne; Gimenez Camino, Naroa; Rabal Gracia, María Obdulia; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.134 N° Supl. 1 2019
  • Autores: Martínez Calle, Nicolás (Autor de correspondencia); Rodríguez Otero, Paula; Villar Fernández, Sara; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.103 N° 7 2018 págs. E318 - E321
  • Autores: Herrero, D.; Canon, S. ; Pelacho Samper, Beatriz; et al.
    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: Rutherford, S. C.; Fachel, A. A.; Li, S. ; et al.
    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: Carazo Melo, Fernando; Romero Riojas, Juan Pablo; Rubio Díaz-Cordoves, Ángel (Autor de correspondencia)
    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: Garitano Trojaola, Andoni; San José Enériz, Edurne; Ezponda Itoiz, Teresa; et al.
    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: Zabaleta Lasarte, Nerea; Barberia, M.; Martin-Higueras, C. ; et al.
    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: Rabal Gracia, María Obdulia; Sánchez Arias, Juan Antonio; San José Enériz, Edurne; et al.
    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.
    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: Martín Moreno, Paloma Leticia (Autor de correspondencia); Rifón Roca, José Juan; Errasti Goenaga, Pedro
    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: Sanoja-Flores, L.; Flores-Montero, J. ; Garcés Latre, Juan José; et al.
    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: García Barchino, María José; Sarasquete, M. E.; Panizo Santos, Carlos Manuel; et al.
    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: Beekman , R; Chapaprieta , V; Russiñol, N; et al.
    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: Montalbán-Bravo, G. (Autor de correspondencia); Takahashi, K.; Patel, K.; et al.
    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: Alameda Serrano, Daniel; Vicari, M. ; Lara-Astiaso, D.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.132 N° Supl. 1 2018 págs. 188
  • Autores: Ganan-Gomez, I.; Alfonso Piérola, Ana; Yang, H. ; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.132 N° Supl. 1 2018
  • Autores: Wagener, R.; Schnaudt, C.; Kleinheinz, K.; et al.
    Revista: BRITISH JOURNAL OF HAEMATOLOGY
    ISSN 0007-1048 Vol.182 2018 págs. 43 - 44
  • Autores: Flinn, I. W. ; Montillo, M.; Nagy, Z.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.132 N° Supl. 1 2018
  • Autores: Caamano, M. L. A.; Lozano, J. J. G.; Ageda, C. A.; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.103 N° Supl. 2 2018 págs. 244 - 244
  • Autores: Puig, N.; Paiva, Bruno; Lasa Ventura, Marta; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.132 N° Supl. 1 2018
  • Autores: Dupere-Richer, D.; Li, J. P. ; Maji, S. ; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.132 N° Supl. 1 2018
  • Autores: Paiva, Bruno; Martinez-Cuadron, D.; Bergua-Burgues, J. M.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.132 N° Supl. 1 2018 págs. 433
  • Autores: Cuenca, I.; Sanchez-Vega, B. ; Paiva, Bruno; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.103 N° Supl. 2 2018 págs. 91 - 91
  • Autores: Abaigar, M. ; López Cadenas, F.; Ramos, F. ; et al.
    Revista: HAEMATOLOGICA
    ISSN 0390-6078 Vol.103 N° Supl. 2 2018 págs. 74 - 75
  • Autores: Feliu, J.; Panizo Santos, Carlos Manuel; Marcos Jubilar, María; et al.
    Libro: La clínica y el laboratorio
    2019 págs. 661 - 708
  • Autores: Ezponda Itoiz, Teresa; Alkorta Aranburu, Gorka; Prosper Cardoso, Felipe; et al.
    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.

Proyectos desde 2018

  • Título: Bioingeniería avanzada para el desarrollo del tejido cardiaco y su aplicación al estudio y detección de cardiotoxicidad
    Código de expediente:
    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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: NO
  • Título: New targets and designs to improve CAR-T cell based immunotherapy against pancreatic cancer
    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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: SI
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: SI
  • 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: 01-10-2022
    Importe concedido: 68.715,96 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: SI
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: SI
  • 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 €
    Fondos FEDER: SI
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: SI
  • 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 €
    Fondos FEDER: SI
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: SI
  • 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 €
    Fondos FEDER: SI
  • 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 €
    Fondos FEDER: SI
  • 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 €
    Fondos FEDER: SI
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: SI
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: NO
  • 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 €
    Fondos FEDER: SI
  • 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 €
    Fondos FEDER: NO