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

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2013 May 18

PMID 23680150

Citations 435

Authors

Wendy Beguelin

Relja Popovic

Matt Teater

Yanwen Jiang

Karen L Bunting

Monica Rosen

Hao Shen

Shao Ning Yang

Ling Wang

Teresa Ezponda

Eva Martinez-Garcia

Haikuo Zhang

Yupeng Zheng

Sharad K Verma

Michael T McCabe

Heidi M Ott

Glenn S Van Aller

Ryan G Kruger

Yan Liu

Charles F McHugh

David W Scott

Young Rock Chung

Neil Kelleher

Rita Shaknovich

Caretha L Creasy

Randy D Gascoyne

Kwok-Kin Wong

Leandro Cerchietti

Ross L Levine

Omar Abdel-Wahab

Jonathan D Licht

Olivier Elemento

Ari M Melnick

Affiliations

Soon will be listed here.

Abstract

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.

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References

De S, Shaknovich R, Riester M, Elemento O, Geng H, Kormaksson M . Aberration in DNA methylation in B-cell lymphomas has a complex origin and increases with disease severity. PLoS Genet. 2013; 9(1):e1003137. PMC: 3542081. DOI: 10.1371/journal.pgen.1003137. View

Ci W, Polo J, Cerchietti L, Shaknovich R, Wang L, Yang S . The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL. Blood. 2009; 113(22):5536-48. PMC: 2689052. DOI: 10.1182/blood-2008-12-193037. View

Morin R, Mendez-Lago M, Mungall A, Goya R, Mungall K, Corbett R . Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011; 476(7360):298-303. PMC: 3210554. DOI: 10.1038/nature10351. View

McCabe M, Ott H, Ganji G, Korenchuk S, Thompson C, Van Aller G . EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012; 492(7427):108-12. DOI: 10.1038/nature11606. View

Yu J, Cao Q, Mehra R, Laxman B, Yu J, Tomlins S . Integrative genomics analysis reveals silencing of beta-adrenergic signaling by polycomb in prostate cancer. Cancer Cell. 2007; 12(5):419-31. DOI: 10.1016/j.ccr.2007.10.016. View

Muller J, Hart C, Francis N, Vargas M, Sengupta A, Wild B . Histone methyltransferase activity of a Drosophila Polycomb group repressor complex. Cell. 2002; 111(2):197-208. DOI: 10.1016/s0092-8674(02)00976-5. View

Sneeringer C, Scott M, Kuntz K, Knutson S, Pollock R, Richon V . Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc Natl Acad Sci U S A. 2010; 107(49):20980-5. PMC: 3000297. DOI: 10.1073/pnas.1012525107. View

Shin D, Liu R, Wu W, Waigel S, Zacharias W, Ratajczak M . Global gene expression analysis of very small embryonic-like stem cells reveals that the Ezh2-dependent bivalent domain mechanism contributes to their pluripotent state. Stem Cells Dev. 2011; 21(10):1639-52. PMC: 3376460. DOI: 10.1089/scd.2011.0389. View

Mortazavi A, Williams B, McCue K, Schaeffer L, Wold B . Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 2008; 5(7):621-8. DOI: 10.1038/nmeth.1226. View

10.

Qi W, Chan H, Teng L, Li L, Chuai S, Zhang R . Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A. 2012; 109(52):21360-5. PMC: 3535655. DOI: 10.1073/pnas.1210371110. View

11.

Egle A, Harris A, Bath M, OReilly L, Cory S . VavP-Bcl2 transgenic mice develop follicular lymphoma preceded by germinal center hyperplasia. Blood. 2003; 103(6):2276-83. DOI: 10.1182/blood-2003-07-2469. View

12.

Giannopoulou E, Elemento O . An integrated ChIP-seq analysis platform with customizable workflows. BMC Bioinformatics. 2011; 12:277. PMC: 3145611. DOI: 10.1186/1471-2105-12-277. View

13.

Cattoretti G, Pasqualucci L, Ballon G, Tam W, Nandula S, Shen Q . Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell. 2005; 7(5):445-55. DOI: 10.1016/j.ccr.2005.03.037. View

14.

Su I, Basavaraj A, Krutchinsky A, Hobert O, Ullrich A, Chait B . Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat Immunol. 2002; 4(2):124-31. DOI: 10.1038/ni876. View

15.

Alizadeh A, Eisen M, Davis R, Ma C, Lossos I, Rosenwald A . Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000; 403(6769):503-11. DOI: 10.1038/35000501. View

16.

Beard C, Hochedlinger K, Plath K, Wutz A, Jaenisch R . Efficient method to generate single-copy transgenic mice by site-specific integration in embryonic stem cells. Genesis. 2006; 44(1):23-8. DOI: 10.1002/gene.20180. View

17.

Shih A, Abdel-Wahab O, Patel J, Levine R . The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer. 2012; 12(9):599-612. DOI: 10.1038/nrc3343. View

18.

Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P . Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002; 298(5595):1039-43. DOI: 10.1126/science.1076997. View

19.

Verma S, Tian X, LaFrance L, Duquenne C, Suarez D, Newlander K . Identification of Potent, Selective, Cell-Active Inhibitors of the Histone Lysine Methyltransferase EZH2. ACS Med Chem Lett. 2014; 3(12):1091-6. PMC: 4025676. DOI: 10.1021/ml3003346. View

20.

Knutson S, Wigle T, Warholic N, Sneeringer C, Allain C, Klaus C . A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat Chem Biol. 2012; 8(11):890-6. DOI: 10.1038/nchembio.1084. View