Aguirre-Ena, X. (Xabier)
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- Mutation patterns of 16 genes in primary and secondary acute myeloid leukemia (AML) with normal cytogenetics(2012) Kondo, T. (Toshinori); McDonald, E.J. (Emma Jane); Perez, C. (Cristina); Fernandez-Mercado, M. (Marta); Wainscoat, J.S. (James S.); Pellagatti, A. (Andrea); Davies, C. (Carwyn); Boultwood, J. (Jacqueline); Larrayoz, M.J. (María J.); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Yip, B.H. (Bon Ham); Odero, M.D. (Maria Dolores); Aguirre-Ena, X. (Xabier); Killick, S. (Sally)Abstract 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
- Epigenetic Signatures Associated with Different Levels of Differentiation Potential in Human Stem Cells(Public Library of Science, 2009) Cigudosa, J.C. (Juan Cruz); Roman-Gomez, J. (José); Ballestar, E. (E.); Aranda, P. (P.); Prieto, I. (Inés); Andreu, E.J. (Enrique José); Siebert, R. (Reiner); Esteller, M. (Manel); Prosper-Cardoso, F. (Felipe); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio)The therapeutic use of multipotent stem cells depends on their differentiation potential, which has been shown to be variable for different populations. These differences are likely to be the result of key changes in their epigenetic profiles.
- Downregulation of DBC1 expression in acute lymphoblastic leukaemia is mediated by aberrant methylation of its promoter(American Society of Hematology, 2006) Cordeu, L. (Lucía); Jimenez-Velasco, A. (A.); Roman-Gomez, J. (José); San-Jose-Eneriz, E. (Edurne); Heiniger, A. (A.); Garate, L. (Leire); Vazquez, I. (Iria); Prosper-Cardoso, F. (Felipe); Torres, A. (Antonio); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier)The DBC1 gene is a potential tumour suppressor gene that is commonly hypermethylated in epithelial cancers. We studied the role of promoter hypermethylation in the regulation of DBC1 in acute lymphoblastic leukaemia (ALL) cell lines and 170 ALL patients at diagnosis. Abnormal methylation of DBC1 was observed in all ALL cell lines and in 17% of ALL patients. Moreover, DBC1 methylation was associated with decreased DBC1 expression, while treatment of ALL cells with 5-Aza-2¢-deoxycytidine resulted in demethylation of the promoter and upregulation of DBC1 expression. Fluorescence in situ hybridisation identified the deletion of one allele of DBC1 in some ALL cell lines, which indicated that the lack of DBC1 expression was due to deletion of one allele and methylation of the other. In conclusion, these results demonstrate, for the first time, that the expression of DBC1 is downregulated in a percentage of patients with ALL due to the hypermethylation of its promoter and/or gene deletion.
- Molecular characterization of a t(1;3)(p36;q21) in a patient with MDS. MEL1 is widely expressed in normal tissues, including bone marrow, and it is not overexpressed in the t(1;3) cells(Nature Publishing Group, 2004) Pelicci, P.G. (Pier G.); Lo-Coco, F. (Francesco); Lahortiga, I. (Idoya); Gasparini, P. (P.); Vazquez, I. (Iria); Larrayoz, M.J. (María J.); Belloni, E. (E.); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores); Aguirre-Ena, X. (Xabier)Patients with myeloid malignancies and either the 3q21q26 syndrome or t(1;3)(p36;q21) have been reported to share similar clinicopathological features and a common molecular mechanism for leukemogenesis. Overexpression of MDS1/EVI1 (3q26) or MEL1/PRDM16 (1p36), both members of the PR-domain family, has been directly implicated in the malignant transformation of this subset of neoplasias. The breakpoints in both entities are outside the genes, and the 3q21 region, where RPN1 is located, seems to act as an enhancer. MEL1 has been reported to be expressed in leukemia cells with t(1;3) and in the normal uterus and fetal kidney, but neither in bone marrow (BM) nor in other tissues, suggesting that this gene is specific to t(1;3)-positive MDS/AML. We report the molecular characterization of a t(1;3)(p36;q21) in a patient with MDS (RAEB-2). In contrast to previous studies, we demonstrate that MEL1, the PR-containing form, and MEL1S, the PR-lacking form, are widely expressed in normal tissues, including BM. The clinicopathological features and the breakpoint on 1p36 are different from cases previously described, and MEL1 is not overexpressed, suggesting a heterogeneity in myeloid neoplasias with t(1;3).
- Promoter hypermethylation and global hypomethylation are independent epigenetic events in lymphoid leukemogenesis with opposing effects on clinical outcome(Nature Publishing Group, 2006) Cordeu, L. (Lucía); Jimenez-Velasco, A. (A.); Roman-Gomez, J. (José); San-Jose-Eneriz, E. (Edurne); Heiniger, A. (A.); Garate, L. (Leire); Navarro, G. (Germán); Barrios, M. (M.); Castillejo, J.A. (J.A.); Prosper-Cardoso, F. (Felipe); Torres, A. (Antonio); Aguirre-Ena, X. (Xabier)
- Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia.(Nature Publishing Group, 2012) Vilas, A. (Amaia); Cigudosa, J.C. (Juan Cruz); Roman-Gomez, J. (José); San-Jose-Eneriz, E. (Edurne); Blanco-Prieto, M.J. (María José); Garate, L. (Leire); Martinez-Climent, J.A. (José Ángel); Rifon, J. J. (Jose J.); Ribera, J.M. (José María); Miranda, E. (Estibaliz); Martino-Rodriguez, A. (Alba) de; Garcia-de-Jalon, J.A. (José A.); Prosper-Cardoso, F. (Felipe); Rio, P. (Paula); Segura, V. (Víctor); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier); Abizanda-Sarasa, G. (Gloria); Martin-Subero, J.I. (Jose Ignacio); Moreno, C. (Cristina)Histone deacetylases (HDACs) have been identified as therapeutic targets due to their regulatory function in chromatin structure and organization. Here, we analyzed the therapeutic effect of LBH589, a class I-II HDAC inhibitor, in acute lymphoblastic leukemia (ALL). In vitro, LBH589 induced dose-dependent antiproliferative and apoptotic effects, which were associated with increased H3 and H4 histone acetylation. Intravenous administration of LBH589 in immunodeficient BALB/c-RAG2(-/-)γc(-/-) mice in which human-derived T and B-ALL cell lines were injected induced a significant reduction in tumor growth. Using primary ALL cells, a xenograft model of human leukemia in BALB/c-RAG2(-/-)γc(-/-) mice was established, allowing continuous passages of transplanted cells to several mouse generations. Treatment of mice engrafted with T or B-ALL cells with LBH589 induced an in vivo increase in the acetylation of H3 and H4, which was accompanied with prolonged survival of LBH589-treated mice in comparison with those receiving vincristine and dexamethasone. Notably, the therapeutic efficacy of LBH589 was significantly enhanced in combination with vincristine and dexamethasone. Our results show the therapeutic activity of LBH589 in combination with standard chemotherapy in pre-clinical models of ALL and suggest that this combination may be of clinical value in the treatment of patients with ALL.
- Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas(American Society of Hematology, 2007) Marin, M. (Miguel); Fresquet, V. (Vicente); Beltran, E. (E.); Dyer, M.J.S. (Martin J. S.); Rosenwald, A. (Andreas); Pinkel, D. (Daniel); Karran, E.L. (E. L.); Martinez-Climent, J.A. (José Ángel); Richter, J.A. (José Ángel); Siebert, R. (Reiner); Mestre-Escorihuela, C. (Cinta); Marugan, I. (Isabel); Sanchez, L. (Lydia); Staudt, L.M. (Louis M.); Rubio-Moscardo, F. (Fanny); Climent, J. (Javier); Wheat, L.M. (Luise M.); Prosper-Cardoso, F. (Felipe); Aguirre-Ena, X. (Xabier); Sugimoto, K.J. (Kei-Ji); Garcia, J.F. (José Francisco)Integrative genomic and gene-expression analyses have identified amplified oncogenes in B-cell non-Hodgkin lymphoma (B-NHL), but the capability of such technologies to localize tumor suppressor genes within homozygous deletions remains unexplored. Array-based comparative genomic hybridization (CGH) and gene-expression microarray analysis of 48 cell lines derived from patients with different B-NHLs delineated 20 homozygous deletions at 7 chromosome areas, all of which contained tumor suppressor gene targets. Further investigation revealed that only a fraction of primary biopsies presented inactivation of these genes by point mutation or intragenic deletion, but instead some of them were frequently silenced by epigenetic mechanisms. Notably, the pattern of genetic and epigenetic inactivation differed among B-NHL subtypes. Thus, the P53-inducible PIG7/LITAF was silenced by homozygous deletion in primary mediastinal B-cell lymphoma and by promoter hypermethylation in germinal center lymphoma, the proapoptotic BIM gene presented homozygous deletion in mantle cell lymphoma and promoter hypermethylation in Burkitt lymphoma, the proapoptotic BH3-only NOXA was mutated and preferentially silenced in diffuse large B-cell lymphoma, and INK4c/P18 was silenced by biallelic mutation in mantle-cell lymphoma. Our microarray strategy has identified novel candidate tumor suppressor genes inactivated by genetic and epigenetic mechanisms that substantially vary among the B-NHL subtypes.
- Repetitive DNA hypomethylation in the advanced phase of chronic myeloid leukemia(Elsevier, 2007) Cordeu, L. (Lucía); Jimenez-Velasco, A. (A.); Roman-Gomez, J. (José); San-Jose-Eneriz, E. (Edurne); Heiniger, A. (A.); Garate, L. (Leire); Navarro, G. (Germán); Castillejo, J.A. (J.A.); Cervantes, F. (F.); Prosper-Cardoso, F. (Felipe); Torres, A. (Antonio); Aguirre-Ena, X. (Xabier)Repetitive elements are heavily methylated in normal tissues, but hypomethylated in malignant tissues, driving the global genomic hypomethylation found in cancer. This hypomethylation results in chromosomal instability, a well-characterized feature of the advanced phases of chronic myeloid leukemia (CML). We investigated methylation changes of DNA repetitive elements (LINE1, Alu, Satellite-alpha and Satellite-2) during the progression of CML from chronic phase (CP) to blast crisis (BC). CP-CML samples were significantly more hypomethylated for all repetitive sequences compared with normal samples. Furthermore, a more profound level of hypomethylation was observed among BC samples compared with CP samples. Our data suggest that repetitive DNA hypomethylation are closely associated with CML progression.
- Epigenetic regulation of the non-canonical Wnt pathway in acute myeloid leukemia(Wiley-Blackwell, 2010) Vilas, A. (Amaia); Cervera, J. (Jose); Roman-Gomez, J. (José); San-Jose-Eneriz, E. (Edurne); Martin, V. (Vanesa); Valencia, A. (Ana); Rodriguez-Otero, P. (Paula); Sanz, M.A. (Miguel A.); Prosper-Cardoso, F. (Felipe); Torres, A. (Antonio); Aguirre-Ena, X. (Xabier); Herrera, C. (Concepción)Wnt5a is a member of the Wnt family of proteins that signals through the non-canonical Wnt ⁄ Ca2+pathway to suppress cyclin D1. Deregulation of this pathway has been found in animal models suggesting that it acts as tumour suppressor in acute myeloid leukemia (AML). Although DNA methylation is the main mechanism of regulation of the canonical Wnt pathway in AML, the role of WNT5A abnormalities has never been evaluated in this clinical setting. The methylation status of WNT5A promoter–exon 1 was analyzed by methylation-specific PCR and sequencing in eleven AML-derived cell lines and 252 AML patients. We observed WNT5A hypermethylation in seven cell lines and in 43% (107 ⁄ 252) of AML patients. WNT5A methylation was associated with decreased WNT5A expression (P < 0.001) that was restored after exposure to 5-Aza-2’-deoxycytidine. Moreover, WNT5A hypermethylation correlated with upregulation of CYCLIN D1 expression (P < 0.001). Relapse (15% vs 37%, P < 0.001) and mortality (61% vs 79%, P = 0.004) rates were lower for patients in the non-methylated group. Disease-free survival and overall survival at 6 and 7 years, respectively, were 60% and 27% for unmethylated patients and 20% and 0% for hypermethylated patients (P = 0.0001 and P = 0.04, respectively). Interestingly, significant differences were also observed when the analysis was carried out according to cytogenetic risk groups. We demonstrate that WNT5A, a putative tumor suppressor gene in AML, is silenced by methylation in this disease and that this epigenetic event is associated with upregulation of CYCLIN D1 expression and confers poor prognosis in patients with AML.
- LMO2 expression reflects the different stages of blast maturation and genetic features in B-cell acute lymphoblastic leukemia and predicts clinical outcome(Ferrata Storti Foundation, 2011) Fresquet, V. (Vicente); Bobadilla, M. (Míriam); Roman-Gomez, J. (José); Lossos, I.S. (Izidore S.); Martinez-Climent, J.A. (José Ángel); Aznar, M.A. (María Ángela); Martin-Palanco, V. (Vanesa); Raquel; Prosper-Cardoso, F. (Felipe); Robles, E.F. (Eloy Francisco); Calasanz-Abinzano, M.J. (Maria Jose); Altobelli, G.G. (Giovanna G.); Aguirre-Ena, X. (Xabier); Smeland, E.B. (Erlend B.)BACKGROUND: LMO2 is highly expressed at the most immature stages of lymphopoiesis. In T-lymphocytes, aberrant LMO2 expression beyond those stages leads to T-cell acute lymphoblastic leukemia, while in B cells LMO2 is also expressed in germinal center lymphocytes and diffuse large B-cell lymphomas, where it predicts better clinical outcome. The implication of LMO2 in B-cell acute lymphoblastic leukemia must still be explored. DESIGN AND METHODS: We measured LMO2 expression by real time RT-PCR in 247 acute lymphoblastic leukemia patient samples with cytogenetic data (144 of them also with survival and immunophenotypical data) and in normal hematopoietic and lymphoid cells. RESULTS: B-cell acute lymphoblastic leukemia cases expressed variable levels of LMO2 depending on immunophenotypical and cytogenetic features. Thus, the most immature subtype, pro-B cells, displayed three-fold higher LMO2 expression than pre-B cells, common-CD10+ or mature subtypes. Additionally, cases with TEL-AML1 or MLL rearrangements exhibited two-fold higher LMO2 expression compared to cases with BCR-ABL rearrangements or hyperdyploid karyotype. Clinically, high LMO2 expression correlated with better overall survival in adult patients (5-year survival rate 64.8% (42.5%-87.1%) vs. 25.8% (10.9%-40.7%), P= 0.001) and constituted a favorable independent prognostic factor in B-ALL with normal karyotype: 5-year survival rate 80.3% (66.4%-94.2%) vs. 63.0% (46.1%-79.9%) (P= 0.043). CONCLUSIONS: Our data indicate that LMO2 expression depends on the molecular features and the differentiation stage of B-cell acute lymphoblastic leukemia cells. Furthermore, assessment of LMO2 expression in adult patients with a normal karyotype, a group which lacks molecular prognostic factors, could be of clinical relevance.