EZH2 Is Required for Germinal Center Formation and Somatic EZH2 Mutations Promote Lymphoid Transformation

被引：740

作者：

Beguelin, Wendy ^{[1
]}

Popovic, Relja ^{[4
]}

Teater, Matt ^{[1
,2
]}

Jiang, Yanwen ^{[1
,2
]}

Bunting, Karen L. ^{[1
]}

Rosen, Monica ^{[1
]}

Shen, Hao ^{[1
]}

Yang, Shao Ning ^{[1
]}

Wang, Ling ^{[1
]}

Ezponda, Teresa ^{[4
]}

Martinez-Garcia, Eva ^{[4
]}

Zhang, Haikuo ^{[5
]}

Zheng, Yupeng ^{[6
,7
]}

Verma, Sharad K. ^{[8
]}

McCabe, Michael T. ^{[8
]}

Ott, Heidi M. ^{[8
]}

Van Aller, Glenn S. ^{[8
]}

Kruger, Ryan G. ^{[8
]}

Liu, Yan ^{[8
]}

McHugh, Charles F. ^{[8
]}

Scott, David W. ^{[9
,10
]}

Chung, Young Rock ^{[11
,12
]}

Kelleher, Neil ^{[6
,7
]}

Shaknovich, Rita ^{[1
]}

Creasy, Caretha L. ^{[8
]}

Gascoyne, Randy D. ^{[9
,10
]}

Wong, Kwok-Kin ^{[5
]}

Cerchietti, Leandro ^{[1
,3
]}

Levine, Ross L. ^{[11
,12
]}

Abdel-Wahab, Omar ^{[11
,12
]}

Licht, Jonathan D. ^{[4
]}

Elemento, Olivier ^{[2
]}

Melnick, Ari M. ^{[1
,3
]}

机构：

[1] Weill Cornell Med Coll, Div Hematol Oncol, Dept Med, New York, NY 10021 USA

[2] Weill Cornell Med Coll, Inst Computat Biomed, New York, NY 10021 USA

[3] Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10021 USA

[4] Northwestern Univ, Div Hematol Oncol, Robert H Lurie Comprehens Canc Ctr, Feinberg Sch Med, Chicago, IL 60611 USA

[5] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[6] Northwestern Univ, Chem Life Proc Inst, Dept Chem, Evanston, IL 60208 USA

[7] Northwestern Univ, Chem Life Proc Inst, Dept Mol Biosci, Evanston, IL 60208 USA

[8] GlaxoSmithKline, Oncol R&D, Canc Res, Canc Epigenet Discovery Performance Unit, Collegeville, PA 19426 USA

[9] British Columbia Canc Res Ctr, British Columbia Canc Agcy, Ctr Lymphoid Canc, Dept Pathol, Vancouver, BC V5Z 1L3, Canada

[10] British Columbia Canc Res Ctr, British Columbia Canc Agcy, Ctr Lymphoid Canc, Dept Expt Therapeut, Vancouver, BC V5Z 1L3, Canada

[11] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[12] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10065 USA

来源：

CANCER CELL | 2013年 / 23卷 / 05期

基金：

美国国家科学基金会;

关键词：

B-CELL LYMPHOMA; HISTONE METHYLTRANSFERASE EZH2; EMBRYONIC STEM-CELLS; NON-HODGKIN-LYMPHOMA; EXPRESSION PATTERNS; TRANSGENIC MICE; GROUP PROTEINS; LYSINE; 27; RNA-SEQ; POLYCOMB;

D O I：

10.1016/j.ccr.2013.04.011

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B cells and targeted by somatic mutations in B cell lymphomas. Here, we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GC B cell (GCB)-type diffuse large B cell lymphomas (DLBCLs) are mostly addicted to EZH2 but not the more differentiated activated B cell (ABC)-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting.

引用

页码：677 / 692

页数：16

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