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EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis
- Béguelin, Wendy;
- Teater, Matt;
- Gearhart, Micah D;
- Fernández, María Teresa Calvo;
- Goldstein, Rebecca L;
- Cárdenas, Mariano G;
- Hatzi, Katerina;
- Rosen, Monica;
- Shen, Hao;
- Corcoran, Connie M;
- Hamline, Michelle Y;
- Gascoyne, Randy D;
- Levine, Ross L;
- Abdel-Wahab, Omar;
- Licht, Jonathan D;
- Shaknovich, Rita;
- Elemento, Olivier;
- Bardwell, Vivian J;
- Melnick, Ari M
- et al.
Published Web Location
https://doi.org/10.1016/j.ccell.2016.07.006Abstract
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.
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