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Cancer Cell. 2016 Aug 8;30(2):197-213. doi: 10.1016/j.ccell.2016.07.006.

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

Author information

1
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, 413 E 69(th) Street, New York, NY 10021, USA.
2
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, 413 E 69(th) Street, New York, NY 10021, USA; Institute for Computational Biomedicine, Weill Cornell Medical College, Cornell University, New York, NY 10021, USA.
3
Department of Genetics, Cell Biology, and Development, Developmental Biology Center, Masonic Cancer Center, University of Minnesota, 6-160 Church Street SE, University of Minnesota, Minneapolis, MN 55455, USA.
4
Departments of Pathology and Lymphoid Cancer Research, Centre for Lymphoid Cancer, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.
5
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
6
Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
7
Institute for Computational Biomedicine, Weill Cornell Medical College, Cornell University, New York, NY 10021, USA.
8
Department of Genetics, Cell Biology, and Development, Developmental Biology Center, Masonic Cancer Center, University of Minnesota, 6-160 Church Street SE, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: bardw001@umn.edu.
9
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, 413 E 69(th) Street, New York, NY 10021, USA. Electronic address: amm2014@med.cornell.edu.

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.

PMID:
27505670
PMCID:
PMC5000552
DOI:
10.1016/j.ccell.2016.07.006
[Indexed for MEDLINE]
Free PMC Article

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