New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling

被引：114

作者：

Martin-Subero, Jose I. ^{[1
]}

Kreuz, Markus ^{[2
]}

Bibikova, Marina ^{[3
]}

Bentink, Stefan ^{[4
]}

Ammerpohl, Ole ^{[1
]}

Wickham-Garcia, Eliza ^{[3
]}

Rosolowski, Maciej ^{[2
]}

Richter, Julia ^{[1
]}

Lopez-Serra, Lidia ^{[5
]}

Ballestar, Esteban ^{[5
]}

Berger, Hilmar ^{[2
]}

Agirre, Xabier ^{[6
,7
,8
]}

Bernd, Heinz-Wolfram ^{[9
]}

Calvanese, Vincenzo ^{[5
]}

Cogliatti, Sergio B. ^{[10
]}

Drexler, Hans G. ^{[11
]}

Fan, Jian-Bing ^{[3
]}

Fraga, Mario F. ^{[5
]}

Hansmann, Martin L. ^{[12
]}

Hummel, Michael ^{[13
]}

Klapper, Wolfram ^{[14
]}

Korn, Bernhard ^{[15
]}

Kueppers, Ralf ^{[16
]}

MacLeod, Roderick A. F. ^{[11
]}

Moeller, Peter ^{[17
]}

Ott, German ^{[18
]}

Pott, Christiane ^{[19
]}

Prosper, Felipe ^{[6
,7
,8
]}

Rosenwald, Andreas ^{[18
]}

Schwaenen, Carsten

Schuebeler, Dirk ^{[20
]}

Seifert, Marc ^{[16
]}

Stuerzenhofecker, Benjamin ^{[21
]}

Weber, Michael ^{[20
]}

Wessendorf, Swen

Loeffler, Markus ^{[2
]}

Truemper, Lorenz ^{[21
]}

Stein, Harald ^{[13
]}

Spang, Rainer ^{[4
]}

Esteller, Manel ^{[5
]}

Barker, David ^{[3
]}

Hasenclever, Dirk ^{[2
]}

Siebert, Reiner ^{[1
]}

机构：

[1] Univ Kiel, Univ Hosp Schleswig Holstein, Inst Human Genet, D-24105 Kiel, Germany

[2] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany

[3] Illumina, San Diego, CA USA

[4] Univ Regensburg, Inst Funct Genom, Regensburg, Germany

[5] Spanish Natl Canc Ctr CNIO, Canc Epigenet Lab, Madrid, Spain

[6] Univ Navarra, Fdn Appl Med Res, Div Canc, E-31080 Pamplona, Spain

[7] Univ Navarra, Area Cell Therapy, E-31080 Pamplona, Spain

[8] Univ Navarra, Hematol Serv, Clin Univ, E-31080 Pamplona, Spain

[9] Univ Hosp Schleswig Holsten Campus Lubeck, Inst Pathol, Lubeck, Germany

[10] Kantonsspital St Gallen, Inst Pathol, St Gallen, Switzerland

[11] DSMZ German Collect Microorganisms & Cell Culture, Braunschweig, Germany

[12] Univ Hosp Frankfurt, Inst Pathol, Frankfurt, Germany

[13] Charite, Inst Pathol, D-13353 Berlin, Germany

[14] Univ Kiel, Univ Hosp Schleswig Holsten Campus Kiel, Inst Hematopathol, Kiel, Germany

[15] German Canc Res Ctr, Genom & Prote Core Facil, D-6900 Heidelberg, Germany

[16] Univ Duisburg Essen, Inst Cell Biol Tumor Res, Essen, Germany

[17] Univ Hosp Ulm, Inst Pathol, Ulm, Germany

[18] Univ Wurzburg, Inst Pathol, D-8700 Wurzburg, Germany

[19] Univ Kiel, Univ Hosp Schleswig Holsten Campus Kiel, Dept Med 2, Kiel, Germany

[20] Friedrich Miescher Inst Biomed Res, Basel, Switzerland

[21] Univ Gottingen, Dept Hematol & Oncol, Gottingen, Germany

来源：

BLOOD | 2009年 / 113卷 / 11期

关键词：

DE-NOVO METHYLATION; DNA METHYLATION; DEVELOPMENTAL REGULATORS; INSTRUCTIVE MECHANISM; GENE; EXPRESSION; POLYCOMB; MOUSE; HYPERMETHYLATION; HODGKIN;

D O I：

10.1182/blood-2008-04-152900

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. (Blood. 2009;113:2488-2497)

引用

页码：2488 / 2497

页数：10

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