Nuestros investigadores

María José Larráyoz Ilundáin

Líneas de investigación
BIOLOGÍA MOLECULAR, NEOPLASIAS HEMATOLOGICAS, MARCADORES GENETICOS, GENOMICA: NGS.
Índice H
17, (WoS, 20/08/2018)

Publicaciones científicas más recientes (desde 2010)

Autores: Martínez, Nicolás; Pascual, M.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  Nº 8  2019  págs. 1572 - 1579
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: Ariceta, B.; Manu, A.; Larráyoz, María José; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  Nº S3  2019  págs. 249 - 249
Autores: Vázquez, Iria; Ariceta, B.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 104  Nº S3  2019  págs. 110 - 110
Autores: Sargas, C.; Ayala, R. ; Chillon, C. ; et al.
Revista: ANNALS OF HEMATOLOGY
ISSN 0939-5555  Vol. 98  Nº Suppl. 1  2019  págs. S38 - S39
Autores: García, María José; Sarasquete, M. E.; Panizo, Carlos Manuel; et al.
Revista: JOURNAL OF PATHOLOGY
ISSN 0022-3417  Vol. 245  Nº 1  2018  págs. 61 - 73
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: Gomez-Llonin, A.; Puiggros, A.; Nonell, L.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 103  Nº suppl 2  2018  págs. 217 - 217
Autores: Amarasinghe, H. ; Wojdacz, T.; Rose-Zerilli, M. ; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 181  Nº Supl. 1  2018  págs. 29 - 29
Autores: Espinet, B. ; Ramos, S.; Gomez-Llonin, A.; et al.
Revista: MODERN PATHOLOGY
ISSN 0893-3952  Vol. 31  Nº Supl. 2  2018  págs. 514 - 514
Autores: Collado, R.; Puiggros, A.; López-Guerrero, J. A.; et al.
Revista: CANCER LETTERS
ISSN 0304-3835  Vol. 409  2017  págs. 42 - 48
Although i(17q) [i(17q)] is frequently detected in hematological malignancies, few studies have assessed its clinical role in chronic lymphocytic leukemia (CLL). We recruited a cohort of 22 CLL patients with i(17q) and described their biological characteristics, mutational status of the genes TP53 and IGHV and genomic complexity. Furthermore, we analyzed the impact of the type of cytogenetic anomaly bearing the TP53 defect on the outcome of CLL patients and compared the progression-free survival (PFS) and overall survival (OS) of i(17q) cases with those of a group of 38 CLL patients harboring other 17p aberrations. We detected IGHV somatic hypermutation in all assessed patients, and TP53 mutations were observed in 71.4% of the cases. Patients with i(17q) were more commonly associated with complex karyotypes (CK) and tended to have a poorer OS than patients with other anomalies affecting 17p13 (median OS, 44 vs 120 months, P = 0.084). Regarding chromosomal alterations, significant differences in the median OS were found among groups (P = 0.044). In conclusion, our findings provide new insights regarding i(17q) in CLL and show a subgroup with adverse prognostic features.
Autores: Rio-Machin, A.; Gomez-Lopez, G.; Munoz, J. ; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 31  Nº 9  2017  págs. 2000 - 2005
Autores: Puiggros, A.; Gomez-Llonin, A.; Ramos, S.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl. 2  2017  págs. 422 - 422
Autores: Fernandez-Rodriguez, C.; Ayala, R.; Barragan, E.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl. 2  2017  págs. 278 - 278
Autores: Fernández, Marta; Larráyoz, María José; Vázquez, Iria; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 102  Nº Supl. 2  2017  págs. 46 - 46
Autores: Pellagatti, A.; Roy, S.; Di Genua, C.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 30  Nº 1  2016  págs. 247 - 250
Autores: Palomo, L.; Xicoy, B.; García, O.; et al.
Revista: AMERICAN JOURNAL OF HEMATOLOGY
ISSN 0361-8609  Vol. 91  Nº 2  2016  págs. 185 - 192
Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder with heterogeneous clinical, morphological and genetic characteristics. Clonal cytogenetic abnormalities are found in 20-30% of patients with CMML. Patients with low risk cytogenetic features (normal karyotype and isolated loss of Y chromosome) account for ~80% of CMML patients and often fall into the low risk categories of CMML prognostic scores. We hypothesized that single nucleotide polymorphism arrays (SNP-A) karyotyping could detect cryptic chromosomal alterations with prognostic impact in these subgroup of patients. SNP-A were performed at diagnosis in 128 CMML patients with low risk karyotypes or uninformative results for conventional G-banding cytogenetics (CC). Copy number alterations (CNAs) and regions of copy number neutral loss of heterozygosity (CNN-LOH) were detected in 67% of patients. Recurrent CNAs included gains in regions 8p12 and 21q22 as well as losses in 10q21.1 and 12p13.2. Interstitial CNN-LOHs were recurrently detected in the following regions: 4q24-4q35, 7q32.1-7q36.3, and 11q13.3-11q25. Statistical analysis showed that some of the alterations detected by SNP-A associated with the patients' outcome. A shortened overall survival (OS) and progression free survival (PFS) was observed in cases where the affected size of the genome (considering CNAs and CNN-LOHs) was >11 Mb. In addition, presence of interstitial CNN-LOH was predictive of poor OS. Presence of CNAs (¿1) associated with poorer OS and PFS in the patients with myeloproliferative CMML. Overall, SNP-A analysis increased the diagnostic yield in patients with low risk cytogenetic features or uninformative CC and added prognostic value to this subset of patients.
Autores: Ruiz-Xiville, N.; Morgades, M.; Martin Ramos, L.; et al.
Revista: HAEMATOLOGICA
ISSN 0390-6078  Vol. 101  Nº Supl. 4  2016  págs. 2 - 2
Autores: Adema, V.; Larráyoz, María José; Calasanz, María José; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 171  Nº 1  2015  págs. 137 - 141
Autores: Menezes, J.; Acquadro, F.; Wiseman, M.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 28  Nº 4  2014  págs. 823 - 829
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a very rare disease that currently lacks genomic and genetic biomarkers to assist in its clinical management. We performed whole-exome sequencing (WES) of three BPDCN cases. Based on these data, we designed a resequencing approach to identify mutations in 38 selected genes in 25 BPDCN samples. WES revealed 37-99 deleterious gene mutations per exome with no common affected genes between patients, but with clear overlap in terms of molecular and disease pathways (hematological and dermatological disease). We identified for the first time deleterious mutations in IKZF3, HOXB9, UBE2G2 and ZEB2 in human leukemia. Target sequencing identified 29 recurring genes, ranging in prevalence from 36% for previously known genes, such as TET2, to 12-16% for newly identified genes, such as IKZF3 or ZEB2. Half of the tumors had mutations affecting either the DNA methylation or chromatin remodeling pathways. The clinical analysis revealed that patients with mutations in DNA methylation pathway had a significantly reduced overall survival (P= 0.047). We provide the first mutational profiling of BPDCN. The data support the current WHO classification of the disease as a myeloid disorder and provide a biological rationale for the incorporation of epigenetic therapies for its treatment.
Autores: Saumell, S.; Florensa, L.; Rodríguez-Rivera, M.; et al.
Revista: LEUKEMIA AND LYMPHOMA
ISSN 1042-8194  Vol. 56  Nº 1  2014  págs. 242 - 243
Autores: Pellagatti, A.; Fernández, Marta; Di Genua, C.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 28  Nº 5  2014  págs. 1148 - 1151
Autores: Perez, C.; Martín-Subero, J. I.; Bellosillo, B.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 98  Nº 9  2013  págs. 1414 - 1420
Most DNA methylation studies in classic Philadelphia-negative myeloproliferative neoplasms have been performed on a gene-by-gene basis. Therefore, a more comprehensive methylation profiling is needed to study the implications of this epigenetic marker in myeloproliferative neoplasms. Here, we have analyzed 71 chronic (24 polycythemia vera, 23 essential thrombocythemia and 24 primary myelofibrosis) and 13 transformed myeloproliferative neoplasms using genome-wide DNA methylation arrays. The three types of chronic Philadelphia-negative myeloproliferative neoplasms showed a similar aberrant DNA methylation pattern when compared to control samples. Differentially methylated regions were enriched in a gene network centered on the NF-¿B pathway, indicating that they may be involved in the pathogenesis of these diseases. In the case of transformed myeloproliferative neoplasms, we detected an increased number of differentially methylated regions with respect to chronic myeloproliferative neoplasms. Interestingly, these genes were enriched in a list of differentially methylated regions in primary acute myeloid leukemia and in a gene network centered around the IFN pathway. Our results suggest that alterations in the DNA methylation landscape play an important role in the pathogenesis and leukemic transformation of myeloproliferative neoplasms. The therapeutic modulation of epigenetically-deregulated pathways may allow us to design targeted therapies for these patients.
Autores: Mallo, M.; Del Rey, M.; Ibáñez, M.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 162  Nº 1  2013  págs. 74 - 86
Lenalidomide is an effective drug in low-risk myelodysplastic syndromes (MDS) with isolated del(5q), although not all patients respond. Studies have suggested a role for TP53 mutations and karyotype complexity in disease progression and outcome. In order to assess the impact of complex karyotypes on treatment response and disease progression in 52 lenalidomide-treated patients with del(5q) MDS, conventional G-banding cytogenetics (CC), single nucleotide polymorphism array (SNP-A), and genomic sequencing methods were used. SNP-A analysis (with control sample, lymphocytes CD3+, in 30 cases) revealed 5q losses in all cases. Other recurrent abnormalities were infrequent and were not associated with lenalidomide responsiveness. Low karyotype complexity (by CC) and a high baseline platelet count (>280x109/l) were associated with the achievement of haematological response (P=0020, P=0013 respectively). Unmutated TP53 status showed a tendency for haematological response (P=0061). Complete cytogenetic response was not observed in any of the mutated TP53 cases. By multivariate analysis, the most important predictor for lenalidomide treatment failure was a platelet count <280x109/l (Odds Ratio=617, P=0040). This study reveals the importance of a low baseline platelet count, karyotypic complexity and TP53 mutational status for response to lenalidomide treatment. It supports the molecular study of TP53 in MDS patients treated with lenalidomide.
Autores: Fernández, Marta; Pellagatti, A.; Di Genua, C.; et al.
Revista: BRITISH JOURNAL OF HAEMATOLOGY
ISSN 0007-1048  Vol. 163  Nº 2  2013  págs. 235 - 239
Whole exome sequencing was performed in a patient with myelodysplastic syndrome before and after progression to acute myeloid leukaemia. Mutations in several genes, including SETBP1, were identified following leukaemic transformation. Screening of 328 patients with myeloid disorders revealed SETBP1 mutations in 14 patients (4 center dot 3%), 7 of whom had -7/del(7q) and 3 had i(17)(q10), cytogenetic markers associated with shortened overall survival and increased risk of leukaemic evolution. SETBP1 mutations were frequently acquired at the time of leukaemic evolution, coinciding with increase of leukaemic blasts. These data suggest that SETBP1 mutations may play a role in MDS and chronic myelomonocytic leukaemia disease progression.
Autores: Arenillas, L.; Mallo, M.; Ramos, F.; et al.
Revista: GENES CHROMOSOMES AND CANCER
ISSN 1045-2257  Vol. 52  Nº 12  2013  págs. 1167 - 1177
Cytogenetic aberrations identified by metaphase cytogenetics (MC) have diagnostic, prognostic, and therapeutic implications in myelodysplastic syndromes (MDS). However, in some MDS patients MC study is unsuccesful. Single nucleotide polymorphism array (SNP-A) based karyotyping could be helpful in these cases. We performed SNP-A in 62 samples from bone marrow or peripheral blood of primary MDS with an unsuccessful MC study. SNP-A analysis enabled the detection of aberrations in 31 (50%) patients. We used the copy number alteration information to apply the International Prognostic Scoring System (IPSS) and we observed differences in survival between the low/intermediate-1 and intermediate-2/high risk patients. We also saw differences in survival between very low/low/intermediate and the high/very high patients when we applied the revised IPSS (IPSS-R). In conclusion, SNP-A can be used successfully in PB samples and the identification of CNA by SNP-A improve the diagnostic and prognostic evaluation of this group of MDS patients.
Autores: Aranaz, Paula; et al.
Revista: LEUKEMIA AND LYMPHOMA
ISSN 1042-8194  Vol. 54  Nº 2  2013  págs. 428 - 431
Autores: Maiques-Diaz, A.; Chou, F. S.; Wunderlich, M.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 26  Nº 6  2012  págs. 1329 - 1337
The AML1-ETO fusion protein, which is present in 10-15% of cases of acute myeloid leukemia, is known to repress myeloid differentiation genes through DNA binding and recruitment of chromatin-modifying proteins and transcription factors in target genes. ChIP-chip analysis of human hematopoietic stem/progenitor cells transduced with the AML1-ETO fusion gene enabled us to identify 1168 AML1-ETO target genes, 103 of which were co-occupied by histone deacetylase 1 (HDAC1) and had lost the hyperacetylation mark at histone H4, and 264 showed a K9 trimethylation at histone H3. Enrichment of genes involved in hematopoietic differentiation and in specific signaling pathways was observed in the presence of these epigenetic modifications associated with an 'inactive' chromatin status. Furthermore, AML1-ETO target genes had a significant correlation between the chromatin marks studied and transcriptional silencing. Interestingly, AML1 binding sites were absent on a large number of selected AML1-ETO promoters and an Sp1 binding site was found in over 50% of them. Reversible silencing induced by the fusion protein in the presence of AML1 and/or Sp1 transcription factor binding site was confirmed. Therefore, this study provides a global analysis of AML1-ETO functional chromatin modifications and identifies the important role of Sp1 in the DNA binding pattern of AML1-ETO, suggesting a role for Sp1-targeted therapy in this leukemia subtype.
Autores: Fernández, Marta; Yip, B. H.; Pellagatti, A.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 7  Nº 8  2012  págs. e42334
Acute myeloid leukemia patients with normal cytogenetics (CN-AML) account for almost half of AML cases. We aimed to study the frequency and relationship of a wide range of genes previously reported as mutated in AML (ASXL1, NPM1, FLT3, TET2, IDH1/2, RUNX1, DNMT3A, NRAS, JAK2, WT1, CBL, SF3B1, TP53, KRAS and MPL) in a series of 84 CN-AML cases. The most frequently mutated genes in primary cases were NPM1 (60.8%) and FLT3 (50.0%), and in secondary cases ASXL1 (48.5%) and TET2 (30.3%). We showed that 85% of CN-AML patients have mutations in at least one of ASXL1, NPM1, FLT3, TET2, IDH1/2 and/or RUNX1. Serial samples from 19 MDS/CMML cases that progressed to AML were analyzed for ASXL1/TET2/IDH1/2 mutations; seventeen cases presented mutations of at least one of these genes. However, there was no consistent pattern in mutation acquisition during disease progression. This report concerns the analysis of the largest number of gene mutations in CN-AML studied to date, and provides insight into the mutational profile of CN-AML.
Autores: Barragán, E.; Montesinos, P.; Camos, M.; et al.
Revista: HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
ISSN 0390-6078  Vol. 96  Nº 10  2011  págs. 1470 - 1477
BACKGROUND: Fms-like tyrosine kinase-3 (FLT3) gene mutations are frequent in acute promyelocytic leukemia but their prognostic value is not well established. DESIGN AND METHODS: We evaluated FLT3-internal tandem duplication and FLT3-D835 mutations in patients treated with all-trans retinoic acid and anthracycline-based chemotherapy enrolled in two subsequent trials of the Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA) and Hemato-Oncologie voor Volwassenen Nederland (HOVON) groups between 1996 and 2005. RESULTS: FLT3-internal tandem duplication and FLT3-D835 mutation status was available for 306 (41%) and 213 (29%) patients, respectively. Sixty-eight (22%) and 20 (9%) patients had internal tandem duplication and D835 mutations, respectively. Internal tandem duplication was correlated with higher white blood cell and blast counts, lactate dehydrogenase, relapse-risk score, fever, hemorrhage, coagulopathy, BCR3 isoform, M3 variant subtype, and expression of CD2, CD34, human leukocyte antigen-DR, and CD11b surface antigens. The FLT3-D835 mutation was not significantly associated with any clinical or biological characteristic. Univariate analysis showed higher relapse and lower survival rates in patients with a FLT3-internal tandem duplication, while no impact was observed in relation to FLT3-D835. The prognostic value of the FLT3-internal tandem duplication was not retained in the multivariate analysis. CONCLUSIONS: FLT3-internal tandem duplication mutations are associated with several hematologic features in acute promyelocytic leukemia, in particular with high white blood cell counts, but we were unable to demonstrate an independent prognostic value in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based regimens.
Autores: Boultwood, J.; Perry, J.; Pellagatti, A.; et al.
Revista: LEUKEMIA
ISSN 0887-6924  Vol. 24  Nº 5  2010  págs. 1062 - 1065