EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis

Wendy Béguelin, Matt Teater, Micah D Gearhart, María Teresa Calvo Fernández, Rebecca L. Goldstein, Mariano G. Cárdenas, Katerina Hatzi, Monica Rosen, Hao Shen, Connie M. Corcoran, Michelle Y. Hamline, Randy D. Gascoyne, Ross L. Levine, Omar Abdel-Wahab, Jonathan D. Licht, Rita Shaknovich, Olivier Elemento, Vivian J Bardwell, Ari M. Melnick

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

Abstract

The EZH2 histone methyltransferase mediates the humoral immune response and drives lymphomagenesis through formation of bivalent chromatin domains at critical germinal center (GC) B cell promoters. Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs.

Original languageEnglish (US)
Pages (from-to)197-213
Number of pages17
JournalCancer Cell
Volume30
Issue number2
DOIs
StatePublished - Aug 8 2016

Bibliographical note

Funding Information:
We thank Dr. Alexander Tarakhovsky (Rockefeller University) for sharing the Ezh2 conditional knockout mouse strain, Dr. Ricardo Dalla-Favera (Columbia University) for the IμBcl6 strain, Dr. Haruhiko Koseki (Riken Center, Japan) for sharing the Cbx8 conditional knockout mouse, and Dr. Sebastien Monette for the mouse pathology reports. We thank GlaxoSmithKline for GSK compounds and Fengtian Xue (University of Maryland) for the synthesis of FX1 compound. W.B. was supported by a Charles Revson Senior Fellowship in Biomedical Science and an American Society of Hematology Scholar Award. M.Y.H was supported by NIH 5F30HL093996 , NIH 5T32GM008244 , AHA 0810194Z , and the University of Minnesota Wetzel Fund . V.J.B. is supported by NCI R01 CA071540 and funds from the Minnesota Masonic Charities , and the University of Minnesota Medical School and Office of the Vice President for Research. A.M. is supported by NCI R01 CA187109 and LLS TRP 6141-14 . A.M. is a consultant to Epizyme, and receives research funding (unrelated to the topic of this manuscript) from Janssen , Eli Lilly , GSK , and Roche .

Publisher Copyright:
© 2016 Elsevier Inc.

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