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

176 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

Publisher Copyright:
© 2016 Elsevier Inc.

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