DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia

被引：233

作者：

Oakes, Christopher C. ^{[1
,15
]}

Seifert, Marc ^{[2
]}

Assenovl, Yassen ^{[1
]}

Gu, Lei ^{[3
,4
]}

Przekopowitz, Martina ^{[2
]}

Ruppert, Amy S. ^{[5
]}

Wang, Qi ^{[6
,7
]}

Imbusch, Charles D. ^{[6
,7
]}

Serva, Andrius ^{[8
]}

Koser, Sandra D. ^{[6
,7
]}

Brocks, David ^{[1
]}

Lipka, Daniel B. ^{[1
]}

Bogatyrova, Olga ^{[1
]}

Weichenhan, Dieter ^{[1
]}

Brors, Benedikt ^{[6
,7
]}

Rassenti, Laura ^{[9
]}

Kipp, Thomas J. ^{[9
]}

Mertens, Daniel ^{[10
,11
]}

Zapatka, Marc ^{[8
]}

Lichter, Peter ^{[8
,15
]}

Doehner, Hartmut ^{[11
]}

Kueppers, Ralf

Zenz, Thorsten ^{[12
,13
,14
]}

Stilgenbauer, Stephan ^{[10
]}

Byrd, John C. ^{[5
]}

Plass, Christoph ^{[1
]}

机构：

[1] German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany

[2] Univ Duisburg Essen, Inst Cell Biol Canc Res, Essen, Germany

[3] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA

[4] Boston Childrens Hosp, Div Newborn Med, Boston, MA USA

[5] Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA

[6] German Canc Res Ctr, Div Theoret Bioinformat, Heidelberg, Germany

[7] German Canc Res Ctr, Div Appl Bioinformat, Heidelberg, Germany

[8] German Canc Res Ctr, Div Mol Genet, Heidelberg, Germany

[9] Univ Calif San Diego, Moores Canc Ctr, Dept Med, La Jolla, CA 92093 USA

[10] German Canc Res Ctr, Cooperat Unit Mech Leukemogenesis, Heidelberg, Germany

[11] Univ Ulm, Dept Internal Med 3, D-89069 Ulm, Germany

[12] Natl Ctr Tumor Dis NCT, Dept Translat Oncol, Heidelberg, Germany

[13] German Canc Res Ctr, Heidelberg, Germany

[14] Heidelberg Univ, Dept Med 5, Heidelberg, Germany

[15] Ohio State Univ, Dept Internal Med, Div Hematol, Columbus, OH 43210 USA

来源：

NATURE GENETICS | 2016年 / 48卷 / 03期

基金：

美国国家卫生研究院;

关键词：

CHROMATIN STATE DYNAMICS; TRANSCRIPTION FACTORS; MUTATIONS; METHYLOME; REVEALS; GENES; CLL; ACTIVATION; EVOLUTION; PROLIFERATION;

D O I：

10.1038/ng.3488

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes. We further uncovered that most previously reported tumor specific methylation events are normally present in non-malignant B cells. Instead, we identified a potential pathogenic role for transcription factor dysregulation in CLL, where excess programming by EGR and NFAT with reduced EBF and AP-1 programming imbalances the normal B cell epigenetic program.

引用

页码：253 / 264

页数：12

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