Trümper, L. (Lorenz)

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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.
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    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.