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

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

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

Authors

Wendy Béguelin¹, Matt Teater², Micah D Gearhart³, María Teresa Calvo Fernández¹, Rebecca L Goldstein¹, Mariano G Cárdenas¹, Katerina Hatzi¹, Monica Rosen¹, Hao Shen¹, Connie M Corcoran³, Michelle Y Hamline³, Randy D Gascoyne⁴, Ross L Levine⁵, Omar Abdel-Wahab⁵, Jonathan D Licht⁶, Rita Shaknovich¹, Olivier Elemento⁷, Vivian J Bardwell⁸, Ari M Melnick⁹

Affiliations

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: [email protected].
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: [email protected].

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.

MeSH terms

Animals
Enhancer of Zeste Homolog 2 Protein / metabolism*
Germinal Center / metabolism*
Germinal Center / pathology
Humans
Lymphoma, Large B-Cell, Diffuse / genetics
Lymphoma, Large B-Cell, Diffuse / metabolism*
Lymphoma, Large B-Cell, Diffuse / pathology
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitochondrial Membrane Transport Proteins
Polycomb Repressive Complex 1 / metabolism*
Polycomb-Group Proteins / metabolism
Promoter Regions, Genetic
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-bcl-6 / metabolism*
Repressor Proteins / metabolism*
Transcription, Genetic

Substances

BCL6 protein, human
BCOR protein, human
Bcl6 protein, mouse
Bcor protein, mouse
CBX8 protein, human
Mitochondrial Membrane Transport Proteins
Polycomb-Group Proteins
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-bcl-6
Repressor Proteins
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Ezh2 protein, mouse
Cbx8 protein, mouse
Polycomb Repressive Complex 1

Abstract

MeSH terms

Substances

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