Grupos Investigadores

Líneas de Investigación

  • Definir la patogénesis celular y molecular durante el desarrollo de los síndromes linfoproliferativos B en modelos de ratón modificados genéticamente y en pacientes.
  • Explorar nuevas estrategias terapéuticas en modelos experimentales pre-clínicos de síndromes linfoproliferativos B que puedan trasladarse al tratamiento de pacientes.

Palabras Clave

  • Inmunoquimitoterapia
  • Linfocitos B
  • Linforma difuso de células grandes B (LDCGB/DLBCL)
  • Microambiente tumoral
  • Mieloma múltiple (MM)
  • Modelos murinos experimentales
  • Síndromes linfoproliferativos B

Publicaciones Científicas desde 2018

  • Autores: Halwani, A. S.; Panizo Santos, Carlos Manuel; Isufi, I.; et al.
    ISSN: 1042-8194 Vol.63 N° 4 2022 págs. 821 - 833
    Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma ( #NCT02501473). The study was comprised of a G100 dose escalation (5 or 10 mu g/dose, or 20 mu g/dose for large tumors); a randomized component comparing G100 to G100 plus pembrolizumab; and G100 20 mu g/dose expansion. Adverse events grade >= 3 were uncommon in patients treated with G100, and no unexpected toxicities were observed when combined with pembrolizumab. G100 20 mu g (n = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity.
  • Autores: Eluard, B.; Nuan-Aliman, S.; Faumont, N.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.139 N° 3 2022 págs. 384 - 398
    Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoid malignancy affecting adults. The NF-kappa B transcription factor family is activated by 2 main pathways, the canonical and the alternative NF-kappa B activation pathway, with different functions. The alternative NF-kappa B pathway leads to activation of the transcriptionally active RelB NF-kappa B subunit. Alternative NF-kappa B activation status and its role in DLBCL pathogenesis remain undefined. Here, we reveal a frequent activation of RelB in a large cohort of DLBCL patients and cell lines, independently of their activated B-cell-like or germinal center B-cell-like subtype. RelB activity defines a new subset of patients with DLBCL and a peculiar gene expression profile and mutational pattern. Importantly, RelB activation does not correlate with the MCD genetic subtype, enriched for activated B-cell-like tumors carrying MYD88(L265P) and CD79B mutations that cooperatively activate canonical NF-kappa B, thus indicating that current genetic tools to evaluate NF-kappa B activity in DLBCL do not provide information on the alternative NF-kappa B activation. Furthermore, the newly defined RelB-positive subgroup of patients with DLBCL exhibits a dismal outcome after immunochemotherapy. Functional studies revealed that RelB confers DLBCL cell resistance to DNA damage-induced apoptosis in response to doxorubicin, a genotoxic agent used in the front-line treatment of DLBCL. We also show that RelB positivity is associated with high expression of cellular inhibitor of apoptosis protein 2 (cIAP2). Altogether, RelB activation can be used to refine the prognostic stratification of DLBCL and may contribute to subvert the therapeutic DNA damage response in a segment of patients with DLBCL.
  • Autores: López-Guillermo, A. (Autor de correspondencia); Canales, M. A.; Dlouhy, I.; et al.
    ISSN: 1042-8194 Vol.63 N° 1 2022 págs. 93 - 100
    This is a randomized phase-2 trial aimed to compare consolidation vs. maintenance in untreated patients with follicular lymphoma (FL) responding to induction. 146 patients were enrolled from 25 Spanish institutions (ZAR2007; #NCT00662948). Patients in PR or CR/CR[u] after R-CHOP were randomized 1:1 to Y-90-ibritumomab-tiuxetan 0.4 mCi/kg (arm A) vs. rituximab 375 mg/m(2) every 8 weeks for 2 years (arm B). After a median follow-up of 10.55 years, 53 patients eventually progressed with a 10-year PFS of 50% vs. 56% for patients in arm A and B, respectively (HR = 1.42; p > 0.1). No significant differences were seen in OS (10-year OS 78% vs. 84.5%; HR = 1.39, p > .1). Patients receiving Y-90-ibritumomab-tiuxetan showed higher incidence of second neoplasms than those in arm B (10-year cumulative incidence 18.5 vs. 2%, respectively; p = .038). In conclusion, in FL patients responding to R-CHOP, no significant differences were found between consolidation and maintenance, although with higher late toxicity for consolidation.
  • Autores: Wang, S.; Lee, K.; Gray, S.; et al.
    ISSN: 0305-1048 Vol.50 N° 14 2022 págs. 8093 - 8106
    DNA damage response pathways rely extensively on nuclease activity to process DNA intermediates. Exonuclease 1 (EXO1) is a pleiotropic evolutionary conserved DNA exonuclease involved in various DNA repair pathways, replication, antibody diversification, and meiosis. But, whether EXO1 facilitates these DNA metabolic processes through its enzymatic or scaffolding functions remains unclear. Here, we dissect the contribution of EXO1 enzymatic versus scaffolding activity by comparing Exo1(DA/DA) mice expressing a proven nuclease-dead mutant form of EXO1 to entirely EXO1-deficient Exo1(-)(/)(-) and EXO1 wild type Exo1(+/+) mice. We show that Exo1(DA/DA) and Exo1(-)(/-) mice are compromised in canonical DNA repair processing, suggesting that the EXO1 enzymatic role is important for error-free DNA mismatch and double-strand break repair pathways. However, in non-canonical repair pathways, EXO1 appears to have a more nuanced function. Next-generation sequencing of heavy chain V region in B cells showed the mutation spectra of Exo1(DA/DA) mice to be intermediate between Exo1(+/)(+) and Exo1(-)(/-) mice, suggesting that both catalytic and scaffolding roles of EXO1 are important for somatic hypermutation. Similarly, while overall class switch recombination in Exo1(DA/DA) and Exo1(-)(/-) mice was comparably defective, switch junction analysis suggests that EXO1 might fulfill an additional scaffolding function downstream of class switching. In contrast to Exo1(-)(/)(-) mice that are infertile, meiosis progressed normally in Exo1(DA/DA) and Exo1(+/+) cohorts, indicating that a structural but not the nuclease function of EXO1 is critical for meiosis. However, both Exo1(DA/DA) and Exo1(-)(/)(-) mice displayed similar mortality and cancer predisposition profiles. Taken together, these data demonstrate that EXO1 has both scaffolding and enzymatic functions in distinct DNA repair processes and suggest a more composite and intricate role for EXO1 in DNA metabolic processes and disease.
  • Autores: Cortegano, I.; Rodríguez, M.; Hernangomez, S.; et al.
    ISSN: 1664-3224 Vol.13 2022 págs. 1011607
    Bronchiolitis in children is associated with significant rates of morbidity and mortality. Many studies have been performed using samples from hospitalized bronchiolitis patients, but little is known about the immunological responses from infants suffering from mild/moderate bronchiolitis that do not require hospitalization. We have studied a collection of nasal lavage fluid (NLF) samples from outpatient bronchiolitis children as a novel strategy to unravel local humoral and cellular responses, which are not fully characterized. The children were age-stratified in three groups, two of them (GI under 2-months, GII between 2-4 months) presenting a first episode of bronchiolitis, and GIII (between 4 months and 2 years) with recurrent respiratory infections. Here we show that elevated levels of pro-inflammatory cytokines (IL1 beta, IL6, TNF alpha, IL18, IL23), regulatory cytokines (IL10, IL17A) and IFN gamma were found in the three bronchiolitis cohorts. However, little or no change was observed for IL33 and MCP1, at difference to previous results from bronchiolitis hospitalized patients. Furthermore, our results show a tendency to IL1 beta, IL6, IL18 and TNF alpha increased levels in children with mild pattern of symptom severity and in those in which non RSV respiratory virus were detected compared to RSV+ samples. By contrast, no such differences were found based on gender distribution. Bronchiolitis NLFs contained more IgM, IgG1, IgG3 IgG4 and IgA than NLF from their age-matched healthy controls. NLF from bronchiolitis children predominantly contained neutrophils, and also low frequency of monocytes and few CD4(+) and CD8(+) T cells. NLF from infants older than 4-months contained more intermediate monocytes and B cell subsets, including naive and memory cells. BCR repertoire analysis of NLF samples showed a biased VH1 usage in IgM repertoires, with low levels of somatic hypermutation. Strikingly, algorithmic studies of the mutation profiles, denoted antigenic selection on IgA-NLF repertoires. Our results support the use of NLF samples to analyze immune responses and may have therapeutic implications.
  • Autores: García Lacarte, Marcos; Contreras Grijalba, Sara; Melchor Sanchez, Javier; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 18 2021 págs. 4683
    Simple Summary The PD-1/PD-L1 axis is not only involved in anti-tumour immune evasion of germinal center (GC)-derived diffuse large B cell lymphomas (DLBCL), but also inherently in the fine-tuned regulation of normal GC reactions during humoral immune responses. This checkpoint axis modulates crosstalks between B and T cells that allow positive selection for survival and proliferation. Malignant DLBCL cells may deceive and take advantage of these mechanisms to establish an immunosuppressive microenvironment. This review delves into PD-1/PD-L1 role in the complex inter-cellular interactions from normal GC reactions to DLBCL progression, in order to highlight vulnerabilities that could be targeted by promising combination immunotherapies. Besides a recognized role of PD-1/PD-L1 checkpoint in anti-tumour immune evasion, there is accumulating evidence that PD-1/PD-L1 interactions between B and T cells also play an important role in normal germinal center (GC) reactions. Even when smaller in number, T follicular helper cells (T-FH) and regulatory T (T-FR) or B (Breg) cells are involved in positive selection of GC B cells and may result critical in the lymphoma microenvironment. Here, we discuss a role of PD-1/PD-L1 during tumour evolution in diffuse large B cell lymphoma (DLBCL), a paradigm of GC-derived lymphomagenesis. We depict a progression model, in two phases, where malignant B cells take advantage of positive selection signals derived from correct antigen-presentation and PD-1/PD-L1 inter-cellular crosstalks to survive and initiate tumour expansion. Later, a constant pressure for the accumulation of genetic/epigenetic alterations facilitates that DLBCL cells exhibit higher PD-L1 levels and capacity to secrete IL-10, resembling Breg-like features. As a result, a complex immunosuppressive microenvironment is established where DLBCL cells sustain proliferation and survival by impairing regulatory control of T-FR cells and limiting IL-21-mediated anti-tumour functions of T-FH cells and maximize the use of PD-1/PD-L1 signaling to escape from CD8(+) cytotoxic activity. Integration of these molecular and cellular addictions into a framework may contribute to the better understanding of the lymphoma microenvironment and contribute to the rationale for novel PD-1/PD-L1-based combinational immunotherapies in DLBCL.
  • Autores: Blanco-Luquin, I.; Lázcoz Ripoll, Paula; Celay Leoz, Ion; et al.
    ISSN: 1424-8247 Vol.14 N° 11 2021 págs. 1184
    Neuroblastoma is the most frequent malignant extracranial solid tumor of infancy. The overall objective of this work consists of determining the presence of alterations in the p53/MDM2/p14ARF signaling pathway in neuroblastoma cell lines and deciphering their possible relationship with resistance to known antineoplastic drugs and to differentiation agents. Firstly, we characterized 10 neuroblastoma cell lines for alterations at the p53/MDM2/p14ARF signaling pathway by analysis of TP53 point mutations, MYCN and MDM2 amplification, and p14ARF methylation, homozygous deletions, and expression. Secondly, we chose SK-N-FI (mutated at TP53) and SK-N-Be(2) (wild-type TP53) cell lines, treated them with chemotherapeutic agents (doxorubicin, etoposide, cisplatin, and melphalan) and with two isomers of retinoic acid (RA): (9-cis and all-trans). Finally, we analyzed the distribution of the cell cycle, the induction of apoptosis, and the expression levels of p53, p21, and Bcl-2 in those two cell lines. P14ARF did not present promoter methylation, homozygous deletions, and protein expression in any of the 10 neuroblastoma cell lines. One TP53 point mutation was detected in the SK-N-FI cell line. MYCN amplification was frequent, while most cell lines did not present MDM2 amplification. Treatment of SK-N-FI and SK-N-Be(2) cells with doxorubicin, etoposide, cisplatin, and melphalan increased apoptosis and blocked the cycle in G2/M, while retinoic acid isomers induced apoptosis and decreased the percentage of cells in S phase in TP53 mutated SK-N-FI cells, but not in TP53 wild-type SK-N-Be(2) cells. Treatment with cisplatin, melphalan, or 9-cis RA decreased p53 expression levels in SK-N-FI cells but not in SK-N-Be (2). The expression of p21 was not modified in either of the two cell lines. Bcl-2 levels were reduced only in SK-N-FI cells after treatment with cisplatin. However, treatments with doxorubicin, etoposide, or 9-cis-RA did not modify the levels of this protein in either of the two cell lines. In conclusion, TP53 mutated SK-N-FI cells respond better to the retinoic isomers than TP53 wild-type SK-N-Be(2) cells. Although these are in vitro results, it seems that deciphering the molecular alterations of the p53/MDM2/p14ARF signaling pathway prior to treating patients of neuroblastoma might be useful for standardizing therapies with the aim of improving survival.
  • Autores: Gonzalez-Barca, E.; Capote, F. J.; Gómez-Codina, J.; et al.
    ISSN: 0939-5555 Vol.100 N° 4 2021 págs. 1023 - 1029
    The purpose of this report is to provide long-term follow-up of 38 patients diagnosed of post-transplant lymphoproliferative disease (PTLD) included in a phase 2 clinical trial of first line therapy with rituximab and to evaluate the same therapy in a real world cohort of 21 consecutive patients treated once the trial was closed. Eligible patients were >= 18 years of age with a biopsy-proven CD20 positive B cell PTLD and treatment naive except for reduction of immunosuppression. Treatment consisted in four weekly infusions of rituximab at the standard dose of 375 mg/m(2). Patients in complete remission (CR) were followed without further treatment, and those in partial remission (PR) were treated with another four cycles of weekly rituximab. Median follow-up in the clinical trial was 13.0 years. Disease-specific survival (DSS) at 10 years was 64.7% [95% confidence interval (CI) 48.2-81.2%]. For those patients who achieved CR (61%), DSS at 5 and 10 years was 94.4% (95% CI 83.8-100%) and 88.1% (95% CI 72.6-100%), respectively, and only 1 patient progressed beyond 5 years. The median follow-up of the real world patients was 6.5 years. DSS at 5 years was 75.2% (95% CI 56.4-94.0%). DSS at 5 years of patients who achieved CR (38%) was 87.5% (95% CI 64.6-100%). In conclusion, PTLD patients in CR after rituximab have an excellent long-term outcome. These results not only apply in the clinical trial setting but are also reproducible in the real world. However, those patients who do not respond represent an unmet clinical need and should be included in prospective clinical trials.
  • Autores: Magid Diefenbach, C. S.; Abrisqueta, P.; González-Barca, E.; et al.
    ISSN: 0732-183X Vol.39 N° 15 2021
  • Autores: Bueno-Costa, A.; Pineyro, D.; Soler, M. ; et al.
    Revista: LEUKEMIA
    ISSN: 0887-6924 Vol.34 N° 4 2020 págs. 1158 - 1162
  • Autores: Garcia-Munoz, R.; Quero, C. ; Perez-Persona, E.; et al.
    ISSN: 0007-1048 Vol.188 N° 5 2020 págs. 661 - 673
    Rituximab is a standard treatment for non-Hodgkin diffuse large B-cell (DLBCL) and follicular (FL) lymphomas. A subcutaneous formulation was developed to improve the resource use of intravenous rituximab, with comparable efficacy and safety profiles except for increased administration-related reactions (ARRs). MabRella was a phase IIIb trial to assess the safety of switching from intravenous to subcutaneous administration of rituximab during first-line induction/maintenance for DLBCL or FL, focusing on ARRs. Efficacy, satisfaction and quality of life were also assessed. Patients received subcutaneous rituximab plus standard induction chemotherapy for DLBCL or FL for 4-7 cycles, and/or every 2 months maintenance monotherapy for FL for 6-12 cycles. The study included 140 patients: DLBCL, n = 29; FL, n = 111. Ninety-five percent of patients experienced adverse events, reaching grade >= 3 in 38 center dot 6% and were serious in 30 center dot 0%. AARs occurred in 48 center dot 6%, mostly (84 center dot 9%) at the injection site, with only 2 center dot 1% of patients reaching grade 3. The end-of-induction complete/unconfirmed complete response rate was 69 center dot 6%. After a median follow-up of 33 center dot 5 months, median disease-/event-/progression-free and overall survivals were not attained. The Rituximab Administration Satisfaction Questionnaire showed improvements in overall satisfaction and the EuroQoL-5D a good quality-of-life perception at induction/maintenance end. Therefore, switching to subcutaneous rituximab showed no new safety issues and maintained efficacy with improved satisfaction and quality of life.
  • Autores: Bastos-Oreiro, M. (Autor de correspondencia); Muntanola, A. ; Panizo Santos, Carlos Manuel; et al.
    ISSN: 0939-5555 Vol.99 N° 4 2020 págs. 799 - 808
    Lymphomas are a large, heterogeneous group of neoplasms with well-defined characteristics, and this heterogeneity highlights the importance of epidemiological data. Knowledge of local epidemiology is essential to optimise resources, design clinical trials, and identify minority entities. Given there are few published epidemiological data on lymphoma in Spain, the Spanish Lymphoma and Autologous Bone Marrow Transplant Group created the RELINF project. The aim of this project is to determine the frequencies and distribution of lymphoid neoplasms in Spain and to analyse survival. We developed an online platform for the prospective collection of data on newly diagnosed cases of lymphoma in Spain between January 2014 and July 2018; 11,400 patients were registered. Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) were the most frequent lymphomas in our series. Marginal B cell lymphoma frequency was higher than that reported in other studies, representing more than 11% of mature B cell lymphomas. Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) was the most common subtype of T cell lymphoma, and NK/T cell lymphomas were more frequent than expected (5.4% of total). Hodgkin's lymphoma accounted for 12% of lymphoproliferative syndromes. Overall survival was greater than 90% at 2 years for indolent B cell lymphomas, and approximately 60% for DLBCL, somewhat lower than that previously reported. Survival was poor for PTCL-NOS and angioimmunoblastic T cell lymphoma, as expected; however, it was somewhat better than that in other studies for anaplastic large cell anaplastic lymphoma kinase lymphomas. This is the first prospective registry to report the frequencies, distribution, and survival of lymphomas in Spain. The frequencies and survival data we report here are globally consistent with that reported in other Western countries. These updated frequencies and survival statistics are necessary for developing appropriate management strategies for neoplasias in the Spanish population.
  • Autores: López Díaz de Cerio, Ascensión; Garcia-Munoz, R.; Pena Carbó, Esther; et al.
    ISSN: 0007-1048 Vol.189 N° 6 2020 págs. 1064 - 1073
    Anti-cluster of differentiation 20 (CD20) monoclonal antibodies (mAbs) have shown promise in follicular lymphoma (FL) as post-induction therapy, by enhancing antibody-dependent cellular cytotoxicity (ADCC). However, cytotoxic cells are reduced after this treatment. We hypothesised thatex vivoexpanded lymphokine-activated killer (LAK) cells administered to FL-remission patients are safe and improve anti-CD20 efficacy. This open, prospective, phase II, single-arm study assessed safety and efficacy ofex vivoexpanded LAK cells in 20 FL-remission patients following rituximab maintenance. Mononuclear cells were obtained in odd rituximab cycles and stimulated with interleukin 2 (IL-2) for 8 weeks, after which >5 x 10(8)LAK cells were injected. Patients were followed-up for 5 years. At the end of maintenance, peripheral blood cells phenotype had not changed markedly. Natural killer, LAK and ADCC activities of mononuclear cells increased significantly after recombinant human IL-2 (rhIL-2) stimulation in all cycles. Rituximab significantly enhanced cytotoxic activity. No patients discontinued treatment. There were no treatment-related serious adverse events. Three patients had progressed by the end of follow-up. After a median (interquartile range) follow-up of 59.4 (43.8-70.9) months, 85% of patients remained progression free. No deaths occurred. Quality-of-life improved throughout the study. Post-induction LAK cells with rituximab seem safe in the long term. Larger studies are warranted to confirm efficacy.
  • Autores: Balinas-Gavira, C.; Rodriguez, M. I.; Andrades, A. ; et al.
    Revista: LEUKEMIA
    ISSN: 0887-6924 Vol.34 N° 10 2020 págs. 2722 - 2735
    Mutations in genes encoding subunits of the SWI/SNF chromatin remodeling complex are frequently found in different human cancers. While the tumor suppressor function of this complex is widely established in solid tumors, its role in hematologic malignancies is largely unknown. Recurrent point mutations inBCL7Agene, encoding a subunit of the SWI/SNF complex, have been reported in diffuse large B-cell lymphoma (DLBCL), but their functional impact remains to be elucidated. Here we show that BCL7A often undergoes biallelic inactivation, including a previously unnoticed mutational hotspot in the splice donor site of intron one. The splice site mutations render a truncated BCL7A protein, lacking a portion of the amino-terminal domain. Moreover, restoration of wild-type BCL7A expression elicits a tumor suppressor-like phenotype in vitro and in vivo. In contrast, splice site mutations block the tumor suppressor function of BCL7A by preventing its binding to the SWI/SNF complex. We also show that BCL7A restoration induces transcriptomic changes in genes involved in B-cell activation. In addition, we report that SWI/SNF complex subunits harbor mutations in more than half of patients with germinal center B-cell (GCB)-DLBCL. Overall, this work demonstrates the tumor suppressor function of BCL7A in DLBCL, and highlights that the SWI/SNF complex plays a relevant role in DLBCL pathogenesis.
  • Autores: Carpio, C. (Autor de correspondencia); Bouabdallah, R. ; Ysebaert, L.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.135 N° 13 2020 págs. 996 - 1007
    Treatment options for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are limited, with no standard of care; prognosis is poor, with 4- to 6-month median survival. Avadomide (CC-122) is a cereblon-modulating agent with immunomodulatory and direct antitumor activities. This phase 1 dose-expansion study assessed safety and clinical activity of avadomide monotherapy in patients with de novo R/R DLBCL and transformed lymphoma. Additionally, a novel gene expression classifier, which identifies tumors with a high immune cell infiltration, was shown to enrich for response to avadomide in R/R DLBCL. Ninety-seven patients with R/R DLBCL, including 12 patients with transformed lymphoma, received 3 to 5 mg avadomide administered on continuous or intermittent schedules until unacceptable toxicity, disease progression, or withdrawal. Eighty-two patients (85%) experienced >= 1 grade 3/4 treatment-emergent adverse events (AEs), most commonly neutropenia (51%), infections (24%), anemia (12%), and febrile neutropenia (10%). Discontinuations because of AEs occurred in 10% of patients. Introduction of an intermittent 5/7-day schedule improved tolerability and reduced frequency and severity of neutropenia, febrile neutropenia, and infections. Among 84 patients with de novo R/R DLBCL, overall response rate (ORR) was 29%, including 11% complete response (CR). Responses were cell-of-origin in- dependent. Classifier-positive DLBCL patients (de novo) had an ORR of 44%, median progression-free survival (mPFS) of 6 months, and 16% CR vs an ORR of 19%, mPFS of 1.5 months, and 5% CR in classifier-negative patients (P = .0096). Avadomide is being evaluated in combination with other antilymphoma agents.
  • Autores: Bartholdy, B. A.; Wang, X. H. ; Yan, X. J.; et al.
    ISSN: 2473-9529 Vol.4 N° 5 2020 págs. 893 - 905
    Intraclonal subpopulations of circulating chronic lymphocytic leukemia (CLL) cells with different proliferative histories and reciprocal surface expression of CXCR4 and CD5 have been observed in the peripheral blood of CLL patients and named proliferative (PF), intermediate (IF), and resting (RF) cellular fractions. Here, we found that these intraclonal circulating fractions share persistent DNA methylation signatures largely associated with the mutation status of the immunoglobulin heavy chain locus (IGHV) and their origins from distinct stages of differentiation of antigen-experienced B cells. Increased leukemic birth rate, however, showed a very limited impact on DNA methylation of circulating CLL fractions independent of IGHV mutation status. Additionally, DNA methylation heterogeneity increased as leukemic cells advanced from PF to RF in the peripheral blood. This frequently co-occurred with heterochromatin hypomethylation and hypermethylation of Polycomb-repressed regions in the PF, suggesting accumulation of longevity-associated epigenetic features in recently born cells. On the other hand, transcriptional differences between paired intraclonal fractions confirmed their proliferative experience and further supported a linear advancement from PF to RF in the peripheral blood. Several of these differentially expressed genes showed unique associations with clinical outcome not evident in the bulk clone, supporting the pathological and therapeutic relevance of studying intraclonal CLL fractions. We conclude that independent methylation and transcriptional landscapes reflect both preexisting cell-of-origin fingerprints and more recently acquired hallmarks associated with the life cycle of circulating CLL cells.
  • Autores: Wang, M. (Autor de correspondencia); Rule, S. ; Zinzani, P. L.; et al.
    Revista: LEUKEMIA
    ISSN: 0887-6924 Vol.33 N° 11 2019 págs. 2762 - 2766
  • Autores: Gonzalez-Farre, B.; Ramis-Zaldivar, J. E.; Salmeron-Villalobos, J.; et al.
    ISSN: 0390-6078 Vol.104 N° 9 2019 págs. 1822 - 1829
    Burkitt-like lymphoma with 11q aberration is characterized by pathological features and gene expression profile resembling those of Burkitt lymphoma but lacks the MYC rearrangement and carries an 11q-arm aberration with proximal gains and telomeric losses. Whether this lymphoma is a distinct category or a particular variant of other recognized entities is controversial. To improve the understanding of Burkitt-like lymphoma with 11q aberration we performed an analysis of copy number alterations and targeted sequencing of a large panel of B-cell lymphomarelated genes in 11 cases. Most patients had localized nodal disease and a favorable outcome after therapy. Histologically, they were high grade B-cell lymphoma, not otherwise specified (8 cases), diffuse large B-cell lymphoma (2 cases) and only one was considered as atypical Burkitt lymphoma. All cases had a germinal center B-cell signature and phenotype with frequent LMO2 expression. The patients with Burkitt-like lymphoma with 11q aberration had frequent gains of 12q12-q21.1 and losses of 6q12.1-q21, and lacked common Burkitt lymphoma or diffuse large B-cell lymphoma alterations. Potential driver mutations were found in 27 genes, particularly involving BTG2, DDX3X, ETSI , EP300, and GNA13. However, ID3, TCF3, or CCND3 mutations were absent in all cases. These results suggest that Burkitt-like lymphoma with 11q aberration is a germinal center-derived lymphoma closer to high-grade B-cell lymphoma or diffuse large B-cell lymphoma than to Burkitt lymphoma.
  • Autores: Pascual, M.; Mena-Varas, M. ; Robles Cortes, Eloy Francisco; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.133 N° 22 2019 págs. 2401 - 2412
    Refractory or relapsed diffuse large B-cell lymphoma (DLBCL) often associates with the activated B-cell-like (ABC) subtype and genetic alterations that drive constitutive NF-kappa B activation and impair B-cell terminal differentiation. Here, we show that DNA damage response by p53 is a central mechanism suppressing the pathogenic cooperation of IKK2ca-enforced canonical NF-kappa B and impaired differentiation resulting from Blimp1 loss in ABC-DLBCL lymphomagenesis. We provide evidences that the interplay between these genetic alterations and the tumor microenvironment select for additional molecular addictions that promote lymphoma progression, including aberrant coexpression of FOXP1 and the B-cell mutagenic enzyme activation-induced deaminase, and immune evasion through major histocompatibility complex class II downregulation, PD-L1 upregulation, and T-cell exhaustion. Consistently, PD-1 blockade cooperated with anti-CD20-mediated B-cell cytotoxicity, promoting extended T-cell reactivation and antitumor specificity that improved long-term overall survival in mice. Our data support a pathogenic cooperation among NF-kappa B-driven prosurvival, genetic instability, and immune evasion mechanisms in DLBCL and provide preclinical proof of concept for including PD-1/PD-L1 blockade in combinatorial immunotherapy for ABC-DLBCL.
  • Autores: Wojdacz, T. K. (Autor de correspondencia); Amarasinghe, H. E.; Kadalayil, L.; et al.
    ISSN: 2473-9529 Vol.3 N° 16 2019 págs. 2474 - 2481
    Chronic lymphocytic leukemia patients with mutated immunoglobulin heavy-chain genes (IGHV-M), particularly those lacking poor-risk genomic lesions, often respond well to chemo immunotherapy (CIT). DNA methylation profiling can subdivide early-stage patients into naive B-cell-like CLL (n-CLL), memory B-cell-like CLL (m-CLL), and intermediate CLL (i-CLL), with differing times to first treatment and overall survival. However, whether DNA methylation can identify patients destined to respond favorably to CIT has not been ascertained. We classified treatment-naive patients (n = 605) from 3 UK chemo and CIT clinical trials into the 3 epigenetic subgroups, using pyrosequencing and microarray analysis, and performed expansive survival analysis. The n-CLL, i-CLL, and m-CLL signatures were found in 80% (n = 245/305), 17% (53/305), and 2% (7/305) of IGHV-unmutated (IGHV-U) cases, respectively, and in 9%, (19/216), 50% (108/216), and 41% (89/216) of IGHV-M cases, respectively. Multivariate Cox proportional analysis identified m-CLL as an independent prognostic factor for overall survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.87; P = .018) in CLL4, and for progression-free survival (HR, 0.25; 95% CI, 0.10-0.57; P = .002) in ARCTIC and ADMIRE patients. The analysis of epigenetic subgroups in patients entered into 3 first-line UK CLL trials identifies m-CLL as an independent marker of prolonged survival and may aid in the identification of patients destined to demonstrate prolonged survival after CIT.
  • Autores: Isidoro-Garcia, M.; Garcia-Sanchez, A.; Sanz, C. (Autor de correspondencia); et al.
    ISSN: 1939-4551 Vol.12 N° 8 2019
    Background: Small non-coding RNAs (snRNAs) develop important functions related to epigenetic regulation. YRNAs are snRNAs involved in the initiation of DNA replication and RNA stability that regulate gene expression. They have been related to autoimmune, cancer and inflammatory diseases but never before to allergy. In this work we described for the first time in allergic patients the differential expression profile of YRNAs, their regulatory mechanisms and their potential as new diagnostic and therapeutic targets. Methods: From a previous whole RNAseq study in B cells of allergic patients, differential expression profiles of coding and non-coding transcripts were obtained. To select the most differentially expressed non coding transcripts, fold change and p-values were analyzed. A validation of the expression differences detected was developed in an independent cohort of 304 individuals, 208 allergic patients and 96 controls by using qPCR. Potential binding and retrotransponibility capacity were characterized by in silico structural analysis. Using a novel bioinformatics approach, RNA targets identification, functional enrichment and network analyses were performed. Results: We found that almost 70% of overexpressed non-coding transcripts in allergic patients corresponded to YRNAs. From the three more differentially overexpressed candidates, increased expression was independently confirmed in the peripheral blood of allergic patients. Structural analysis suggested a protein binding capacity decrease and an increase in retrotransponibility. Studies of RNA targets allowed the identification of sequences related to the immune mechanisms underlying allergy. Conclusions: Overexpression of YRNAs is observed for the first time in allergic patients. Structural and functional information points to their implication on regulatory mechanisms of the disease.
  • Autores: García Lacarte, Marcos; Mansego Talavera, María Luisa; Zulet Alzórriz, María de los Ángeles; et al.
    Revista: CELLS
    ISSN: 2073-4409 Vol.8 N° 12 2019
    The aim of the present investigation was to identify putative miRNAs involved in the response to weight loss. Reverse-transcribed RNA isolated from white blood cells (WBCs) of a subpopulation from the Reduction of the Metabolic Syndrome in Navarra-Spain (RESMENA-S) study (low-responders (LR) and high-responders (HR)) was hybridized in a gene expression microarray. Moreover, miRNAs were sequenced by miRNA-Seq. It was found that miR-548q and miR-1185-1 were overexpressed in HR, both in the microarray and in the miRNA-Seq. A bioinformatic prediction of putative target genes of the selected miRNAs found that GSK3B, a putative target for miR-548q and miR-1185-1, was downregulated in HR. Particular 3 '-UTR binding regions of GSK3B were cloned downstream of the firefly luciferase gene. HEK-293T cells were co-transfected with either 0.25 mu g of empty pmiR-GLO or pmiR-GLO-548q-3 '-UTR/pmiR-GLO-1185-1-3 '-UTR, and 7.5 pmol of miR-548q/miR-1185-1 mimics, demonstrating that miR-1185-1 bound to the 3 '-UTR region of GSK3B. THP-1 cells were transfected with either 20/40 nM of miR-548q/miR-1185-1 mimics, evidencing that miR-1185-1inhibited the expression of the gene when transfected at doses of 20/40 nM, whereas miR-548q inhibited GSK3B expression at a dose of 40 nM. As a conclusion, miR-548q and miR-1185-1 levels in WBCs are biomarkers of response to weight-loss diets and could be involved in the regulation of the proinflammatory gene GSK3B.
  • Autores: Garcia-Munoz, R. (Autor de correspondencia); Najera, M. J. ; Feliu, J. ; et al.
    ISSN: 2056-5623 Vol.5 N° 10 2019 págs. FSO425
    Aim: To analyze the effects of subcutaneous or intravenous rituximab + lymphokine-activated killer cells, obinutuzumab or ibrutinib on natural killer (NK) cell levels in chronic lymphocytic leukemia and follicular lymphoma patients. Patients & methods: The distribution of peripheral blood NK cells of 31 patients was analyzed by flow cytometry. Results: We detected a decrease of NK cells in peripheral blood below normal range after obinutuzumab treatment. During maintenance treatment with subcutaneous rituximab, an NK cell reduction was less pronounced than after intravenous rituximab treatment, despite lymphokine-activated killer cell infusions. Conclusion: After one dose of obinutuzumab, each NK cell in peripheral blood destroys 25 leukemic cells. Lay abstract: The standard treatment of chronic lymphocytic leukemia and follicular lymphoma is chemotherapy in combination with anti-CD20 monoclonal antibodies, resulting in the destruction of the immune system, or a Kamikaze effect'. Unfortunately, immunotherapy with rituximab or obinutuzumab may be of limited efficacy when the immunological system is overwhelmed by abundant tumor cells or is diminished by chemotherapy, which eliminates effector immune cells such as natural killer cells before they would be able to kill the whole tumor. Hence, it is important to measure the number of immune cells to ensure that during the encounter of effector cells with tumor cells, sufficient `warriors' can win the battle against the tumor. Otherwise, something akin to the Battle of Thermopylae can happen where a limited number of Spartan warriors faced a huge army and were defeated in the end.
  • Autores: Tamariz Amador, Luis Esteban; Riego Repullo, Victoria; Palacios Berraquero, María Luisa; et al.
    ISSN: 0390-6078 Vol.104 2019 págs. 276 - 277
  • Autores: Diefenbach, C.; Kahl, B. ; Banerjee, L.; et al.
    ISSN: 0732-183X Vol.37 N° 15 2019
  • Autores: Martín Moreno, Paloma Leticia (Autor de correspondencia); Panizo Santos, Carlos Manuel
    ISSN: 1062-4821 Vol.27 N° 6 2018 págs. 440 - 444
    Purpose of review Posttransplant lymphoproliferative disorder (PTLD), frequently associated with Epstein-Barr virus (EBV), is one of the most serious complications leading to worse patient and graft outcomes. Hence, we summarize in this review relevant studies published about PTLD in the last 18 months. Recent findings Recent studies have improved the knowledge about epidemiology, prophylaxis, diagnosis and PTLD treatment. Special interest has developed in improving the last PTLD classification of the World Health Organization, increasing the accuracy of diagnostic tests for EBV viral load quantification and discriminating the genetic differences between PTLD types. There seems to be no real advantage in the use of antiviral drugs for prophylaxis, but better results in therapeutic approaches are being obtained mainly with the use of rituximab with or without chemotherapy, but also with the possibility of using adoptive T-cell therapy or new drugs. Summary PTLD continues being a complication that requires continued effort of the scientific community to reduce its incidence and to develop better diagnostic tests and new strategies that improve results in prophylaxis and treatment.
  • Autores: Herrero Santos, José Ignacio (Autor de correspondencia); Panizo Santos, Carlos Manuel
    ISSN: 1130-0108 Vol.110 N° 2 2018 págs. 131 - 132
  • Autores: Martínez Climent, José Ángel (Autor de correspondencia)
    ISSN: 0390-6078 Vol.103 N° 8 2018 págs. 1252 - 1255
  • Autores: Wang, M. (Autor de correspondencia); Rule, S.; Zinzani, P. L.; et al.
    Revista: LANCET
    ISSN: 0140-6736 Vol.391 N° 10121 2018 págs. 659 - 667
    Background Bruton tyrosine kinase is a clinically validated target in mantle cell lymphoma. Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase inhibitor developed to minimise off-target activity. Methods In this open-label, phase 2 study, oral acalabrutinib (100 mg twice per day) was given to patients with relapsed or refractory mantle cell lymphoma, until disease progression or unacceptable toxicity. The primary endpoint was overall response assessed according to the Lugano classification, and safety analyses were done in all participants. This trial is registered with, number NCT02213926. Findings From March 12, 2015, to Jan 5, 2016, 124 patients with relapsed or refractory mantle cell lymphoma were enrolled and all patients received treatment; median age 68 years. Patients received a median of two (IQR 1-2) previous therapies. At a median follow-up of 15.2 months, 100 (81%)patients achieved an overall response and 49 (40%) patients achieved a complete response. The Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached; the 12-month rates were 72% (95% CI 62-80), 67% (58-75), and 87% (79-92%), respectively. The most common adverse events were primarily grade 1 or 2 and were headache (47 [38%]), diarrhoea (38 [31%]), fatigue (34 [27%]), and myalgia (26 [21%]). The most common grade 3 or worse adverse events were neutropenia (13 [10%]), anaemia (11 [9%]), and pneumonia (six [5%]). There were no cases of atrial fibrillation and one case of grade 3 or worse haemorrhage. The median duration of treatment was 13.8 months. Treatment was discontinued in 54 (44%) patients, primarily due to progressive disease (39 [31%]) and adverse events (seven [6%]). Interpretation Acalabrutinib treatment provided a high rate of durable responses and a favourable safety profile in patients with relapsed or refractory mantle cell lymphoma. These findings suggest an important role for acalabrutinib in the treatment of this disease population.
  • Autores: Wang, M. ; Rule, S. ; Zinzani, P. L.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.132 N° Supl. 1 2018
  • Autores: Bastos Oreiro, M.; Prat, M. ; Panizo Santos, Carlos Manuel; et al.
    ISSN: 0390-6078 Vol.103 N° Supl. 2 2018 págs. 6
  • Autores: Gonzalez-Barca, E. ; Martin, A.; Bello, J. L. ; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.132 N° Supl. 1 2018
  • Autores: Bueno-Costa, A.; Pineyro, D.; Soler, M.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.132 N° Supl. 1 2018
  • Autores: Condorhuaman, L. P. ; Aguinaga, L.; Benitez , R. P.; et al.
    ISSN: 0390-6078 Vol.103 N° Supl. 2 2018 págs. 221 - 222
  • Autores: Flowers, C. R. ; Panizo Santos, Carlos Manuel; Isufi, I.; et al.
    Revista: BLOOD
    ISSN: 0006-4971 Vol.132 N° Supl. 1 2018
  • Autores: Gonzalez-Barca, E. ; Bello, J. L.; Panizo Santos, Carlos Manuel; et al.
    ISSN: 0390-6078 Vol.103 N° Supl. 2 2018 págs. 17

Proyectos desde 2018

  • Título: Programa I3 de incorporación de doctores
    Código de expediente: Programa I3 (2021)
    Investigador principal: SERGIO ROA GOMEZ.
    Convocatoria: 2021 AEI Ayudas para estabilización I3
    Fecha de inicio: 01-12-2021
    Fecha fin: 30-11-2023
    Importe concedido: 100.000,00€
    Otros fondos: -
  • Título: Desarrollo de un test PCR para la detección temprana y prevención de hipomineralización molar-incisiva (MIH) en la población odonto-pediátrica navarra (Hysso-MIH)
    Código de expediente: 0011-1365-2021-000199
    Investigador principal: SERGIO ROA GOMEZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2021 GN I+D Transferencia del conocimiento (empresas)
    Fecha de inicio: 01-04-2021
    Fecha fin: 31-03-2023
    Importe concedido: 120.901,94€
    Otros fondos: -
  • Título: Ayuda Ramón y Cajal
    Código de expediente: RYC-2014-16399
    Investigador principal: SERGIO ROA GOMEZ.
    Convocatoria: 2014 MINECO Ramón y Cajal
    Fecha de inicio: 01-09-2020
    Fecha fin: 30-11-2021
    Importe concedido: 42.150,00€
    Otros fondos: -
    Código de expediente: 0011-0537-2019-000010
    Investigador principal: JAVIER MELCHOR SANCHEZ.
    Fecha de inicio: 01-06-2020
    Fecha fin: 30-04-2023
    Importe concedido: 68.715,96€
    Otros fondos: -
  • Título: Descifrando vulnerabilidades en el microambiente tumoral de los linfomas difusos de células B grandes
    Código de expediente: PID2020-112994RB-I00
    Investigador principal: SERGIO ROA GOMEZ.
    Convocatoria: 2020 AEI PROYECTOS I+D+i (incluye Generación del conocimiento y Retos investigación)
    Fecha de inicio: 01-01-2019
    Fecha fin: 30-08-2024
    Importe concedido: 220.946,00€
    Otros fondos: -
    Código de expediente: SAF2017-82309-R
    Investigador principal: SERGIO ROA GOMEZ.
    Convocatoria: 2017 MINECO RETOS
    Fecha de inicio: 01-01-2018
    Fecha fin: 30-09-2021
    Importe concedido: 169.400,00€
    Otros fondos: Fondos FEDER
  • Título: MINECO IJCI-2015-26742
    Código de expediente: IJCI-2015-26742
    Investigador principal: MARTA LARRAYOZ ILUNDAIN.
    Convocatoria: 2015 - JUAN DE LA CIERVA INCORPORACION
    Fecha de inicio: 26-06-2017
    Fecha fin: 30-11-2018
    Importe concedido: 64.000,00€
    Otros fondos: Fondos FEDER
  • Título: Papel de la proteína homeobox NKX2-3 en la biología y terapia de los linfomas B de la zona marginal
    Código de expediente: PI16/00581
    Investigador principal: JOSE ANGEL MARTINEZ CLIMENT.
    Convocatoria: 2016 - PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 01-01-2017
    Fecha fin: 31-12-2019
    Importe concedido: 236.252,50€
    Otros fondos: Fondos FEDER
  • Título: MINECO IJCI-2014-22507
    Código de expediente: IJCI-2014-22507
    Investigador principal: ION CELAY LEOZ.
    Fecha de inicio: 11-11-2016
    Fecha fin: 10-11-2018
    Importe concedido: 64.000,00€
    Otros fondos: Fondos FEDER
  • Título: ¿Molecular mechanisms of DNA editing and genomic instability through DNA deamination¿
    Código de expediente: RYC-2014-16399
    Investigador principal: SERGIO ROA GOMEZ.
    Convocatoria: 2014 - MINECO RAMON Y CAJAL
    Fecha de inicio: 09-04-2016
    Fecha fin: 01-07-2021
    Importe concedido: 208.600,00€
    Otros fondos: Fondos FEDER
  • Título: Early detection and intervention: Understanding the mechanisms of transformation and hidden resistance of incurable haematological malignancies
    Código de expediente: C355/A26819
    Convocatoria: Accelerator Grant 2017
    Fecha de inicio: 01-12-2018
    Fecha fin: 30-11-2023
    Importe concedido: 764.889,66€
    Otros fondos: -
  • Título: NKX2-3: Understanding how homeobox protein NKX2-3 triggers B-cell receptor signaling and promotes marginal-zone lymphomagenesis
    Código de expediente: 15-1322
    Investigador principal: JOSE ANGEL MARTINEZ CLIMENT
    Convocatoria: WCR OCTUBRE 2014
    Fecha de inicio: 01-10-2015
    Fecha fin: 30-09-2018
    Importe concedido: 174.332,43€
    Otros fondos: -
  • Título: Preclinical in vivo study of the role of the autocrine IL-10/JAK1/STAT3 cascade in the pro-survival signaling and anti-tumor immune evasion of diffuse large B-cell lymphomas
    Investigador principal: SERGIO ROA GOMEZ
    Financiador: GILEAD SCIENCES, S.L.
    Convocatoria: FIMA GILEAD 2019
    Fecha de inicio: 16-12-2019
    Fecha fin: 15-12-2021
    Importe concedido: 49.997,20€
  • Título: A genetically engineered mouse model of multiple myeloma as a tool to understand plasma cell malignant transformation and to cure the disease.
    Investigador principal: MARTA LARRAYOZ ILUNDAIN
    Convocatoria: Investigador AECC 2018, Investigador AECC 2018, Investigador AECC 2018
    Fecha de inicio: 01-12-2018
    Fecha fin: 28-02-2023
    Importe concedido: 212.500,00€
  • Título: Inhibición de la proteína reguladora del metabolismo iónico SLC4A2 como nueva terapia en neoplasias linfoides
    Investigador principal: JOSE ANGEL MARTINEZ CLIMENT
    Convocatoria: 2014 - FUNDACION RAMON ARECES
    Fecha de inicio: 07-04-2015
    Fecha fin: 06-04-2018
    Importe concedido: 125.000,00€