Richter, J. (Julia)
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- A Comprehensive Microarray-Based DNA Methylation Study of 367 Hematological Neoplasms(Public Library of Science, 2009) Cigudosa, J.C. (Juan Cruz); Stein, H. (Harald); Ammerpohl, O. (Ole); Dreyling, M. (Martin); Richter, J. (Julia); Trümper, L. (Lorenz); Montesinos-Rongen, M. (Manuel); Roman-Gomez, J. (José); Dyer, M.J.S. (Martin J. S.); Alvarez, S. (Sara); Bug, S. (Stefanie); Dürig, J. (Jan); Nagel, I. (Inga); Seifert, M. (Marc); Gesk, S. (Stefan); Bibikova, M. (Marina); Küppers, R. (Ralf); Harder, L. (Lana); Klapper, W. (Wolfram); Brüggemann, M. (Monika); Siebert, R. (Reiner); Vater, I. (Inga); Haferlach, C. (Claudia); Deckert, M. (Martina); Wickham, E. (Eliza); Du, M.Q. (Ming Q.); Hansmann, M.L. (Martin-Leo); Potter, K. (Kathleen N.); Prosper-Cardoso, F. (Felipe); Fan, J.B. (Jian-Bing); Calasanz-Abinzano, M.J. (Maria Jose); Hartmann, S. (Sylvia); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio); Suela, J. (Javier)Background: Alterations in the DNA methylation pattern are a hallmark of leukemias and lymphomas. However, most epigenetic studies in hematologic neoplasms (HNs) have focused either on the analysis of few candidate genes or many genes and few HN entities, and comprehensive studies are required. Methodology/Principal Findings: Here, we report for the first time a microarray-based DNA methylation study of 767 genes in 367 HNs diagnosed with 16 of the most representative B-cell (n = 203), T-cell (n = 30), and myeloid (n = 134) neoplasias, as well as 37 samples from different cell types of the hematopoietic system. Using appropriate controls of B-, T-, or myeloid cellular origin, we identified a total of 220 genes hypermethylated in at least one HN entity. In general, promoter hypermethylation was more frequent in lymphoid malignancies than in myeloid malignancies, being germinal center mature B-cell lymphomas as well as B and T precursor lymphoid neoplasias those entities with highest frequency of geneassociated DNA hypermethylation. We also observed a significant correlation between the number of hypermethylated and hypomethylated genes in several mature B-cell neoplasias, but not in precursor B- and T-cell leukemias. Most of the genes becoming hypermethylated contained promoters with high CpG content, and a significant fraction of them are targets of the polycomb repressor complex. Interestingly, T-cell prolymphocytic leukemias show low levels of DNA hypermethylation and a comparatively large number of hypomethylated genes, many of them showing an increased gene expression. Conclusions/Significance: We have characterized the DNA methylation profile of a wide range of different HNs entities. As well as identifying genes showing aberrant DNA methylation in certain HN subtypes, we also detected six genes—DBC1, DIO3, FZD9, HS3ST2, MOS, and MYOD1—that were significantly hypermethylated in B-cell, T-cell, and myeloid malignancies. These might therefore play an important role in the development of different HNs.
- Hypermethylation of the alternative AWT1 promoter in hematological malignancies is a highly specific marker for acute myeloid leukemias despite high expression levels(2014) Richter, J. (Julia); Kwon, M. (Mi); Court, F. (Franck); Buño, I. (Ismael); Catala, A. (Albert); Siebert, R. (Reiner); Esteller, M. (Manel); Monk, D. (David); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores); Guillaumet-Adkins, A. (Amy); Aguirre-Ena, X. (Xabier); Sandoval, J. (Juan)Abstract Background: Wilms tumor 1 (WT1) is over-expressed in numerous cancers with respect to normal cells, and has either a tumor suppressor or oncogenic role depending on cellular context. This gene is associated with numerous alternatively spliced transcripts, which initiate from two different unique first exons within the WT1 and the alternative (A)WT1 promoter intervals. Within the hematological system, WT1 expression is restricted to CD34+/ CD38- cells and is undetectable after differentiation. Detectable expression of this gene is an excellent marker for minimal residual disease in acute myeloid leukemia (AML), but the underlying epigenetic alterations are unknown. Methods: To determine the changes in the underlying epigenetic landscape responsible for this expression, we characterized expression, DNA methylation and histone modification profiles in 28 hematological cancer cell lines and confirmed the methylation signature in 356 cytogenetically well-characterized primary hematological malignancies. Results: Despite high expression of WT1 and AWT1 transcripts in AML-derived cell lines, we observe robust hypermethylation of the AWT1 promoter and an epigenetic switch from a permissive to repressive chromatin structure between normal cells and AML cell lines. Subsequent methylation analysis in our primary leukemia and lymphoma cohort revealed that the epigenetic signature identified in cell lines is specific to myeloid-lineage malignancies, irrespective of underlying mutational status or translocation. In addition to being a highly specific marker for AML diagnosis (positive predictive value 100%; sensitivity 86.1%; negative predictive value 89.4%), we show that AWT1 hypermethylation also discriminates patients that relapse from those achieving complete remission after hematopoietic stem cell transplantation, with similar efficiency to WT1 expression profiling. Conclusions: We describe a methylation signature of the AWT1 promoter CpG island that is a promising marker for classifying myeloid-derived leukemias. In addition AWT1 hypermethylation is ideally suited to monitor the recurrence of disease during remission in patients undergoing allogeneic stem cell transfer.
- Epigenetic activation of SOX11 in lymphoid neoplasms by histone modifications(Public Library of Science, 2011) Jares, P. (Pedro); Salaverria-Lete, I. (Itziar); Richter, J. (Julia); Roman-Gomez, J. (José); Xargay-Torrent, S. (Silvia); Rosenwald, A. (Andreas); Ott, G. (German); Enjuanes, A. (Anna); Bea, S. (Silvia); Palomero, J. (Jara); Royo, C. (Cristina); Martin-Guerrero, I. (Idoia); Hernandez, L. (Luis); Amador, V. (Virginia); Campo, E. (Elías); Siebert, R. (Reiner); Balint, B. (Balazs); Lujambio, A. (Amaya); Esteller, M. (Manel); Vegliante, M.C. (Maria Carmela); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio)Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications
- Biallelic inactivation of TRAF3 in a subset of B-cell lymphomas with interstitial del(14)(q24.1q32.33)(Nature Publishing Group, 2009) Tönnies, H. (Holger); Ammerpohl, O. (Ole); Richter, J. (Julia); Dyer, M.J.S. (Martin J. S.); Bastard, C. (C.); Bug, S. (Stefanie); Martinez-Climent, J.A. (José Ángel); Nagel, I. (Inga); Gesk, S. (Stefan); Harder, L. (Lana); Callet-Bauchu, E. (E.); Siebert, R. (Reiner); Vater, I. (Inga); Schroers, E. (E.); Calasanz-Abinzano, M.J. (Maria Jose); Salido, M. (Marta); Majid, A. (Aneela); Martin-Subero, J.I. (Jose Ignacio)
- New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling(American Society of Hematology, 2009) Stürzenhofecker, B. (Benjamin); Cogliatti, S. (S.B.); Stein, H. (Harald); Ammerpohl, O. (Ole); Hasenclever, D. (D.); Richter, J. (Julia); Korn, B. (Bernhard); Trümper, L. (Lorenz); Kreuz, M. (Markus); Berger, H. (H.); Rosenwald, A. (Andreas); Drexler, H.G. (Hans G.); Ott, G. (German); Loeffler, M. (Markus); Weber, M. (Michael); Schübeler, D. (Dirk); Bentink, S. (S.); Ballestar, E. (E.); Fraga, M.F. (Mario F.); Bernd, H.W (H.W.); Seifert, M. (Marc); Möller, P. (Peter); Bibikova, M. (Marina); Küppers, R. (Ralf); Klapper, W. (Wolfram); Siebert, R. (Reiner); Barker, D. (D.); Esteller, M. (Manel); Wessendorf, S. (Swen); Wickham, E. (Eliza); Hummel, M. (M.); Rosolowski, M. (Maciej); Schwaenen, C. (Carsten); Hansmann, M.L. (Martin-Leo); Potter, K. (Kathleen N.); Prosper-Cardoso, F. (Felipe); Spang, R. (Rainer); Fan, J.B. (Jian-Bing); Calvanese, V. (V.); Lopez-Serra, L. (Lidia); MacLeod, R.A.F. (Roderick A.F.); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio)Lymphomas are assumed to originate at different stages of lymphocyte development through chromosomal aberrations. Thus, different lymphomas resemble lymphocytes at distinct differentiation stages and show characteristic morphologic, genetic, and transcriptional features. Here, we have performed a microarray-based DNA methylation profiling of 83 mature aggressive B-cell non-Hodgkin lymphomas (maB-NHLs) characterized for their morphologic, genetic, and transcriptional features, including molecular Burkitt lymphomas and diffuse large B-cell lymphomas. Hierarchic clustering indicated that methylation patterns in maB-NHLs were not strictly associated with morphologic, genetic, or transcriptional features. By supervised analyses, we identified 56 genes de novo methylated in all lymphoma subtypes studied and 22 methylated in a lymphoma subtype–specific manner. Remarkably, the group of genes de novo methylated in all lymphoma subtypes was significantly enriched for polycomb targets in embryonic stem cells. De novo methylated genes in all maB-NHLs studied were expressed at low levels in lymphomas and normal hematopoietic tissues but not in nonhematopoietic tissues. These findings, especially the enrichment for polycomb targets in stem cells, indicate that maB-NHLs with different morphologic, genetic, and transcriptional background share a similar stem cell–like epigenetic pattern. This suggests that maB-NHLs originate from cells with stem cell features or that stemness was acquired during lymphomagenesis by epigenetic remodeling.