title: EZH2 and BCL6 Cooperate to Assemble CBX8-BCOR Complex to Repress Bivalent Promoters, Mediate Germinal Center Formation and Lymphomagenesis.
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.
authors: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, 413 E 69(th) Street, New York, NY 10021, USA.
authors: Wendy
authors: W
authors: Béguelin
authors: 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.
authors: Matt
authors: M
authors: Teater
authors: 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.
authors: Micah D
authors: MD
authors: Gearhart
authors: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, 413 E 69(th) Street, New York, NY 10021, USA.
authors: María Teresa
authors: MT
authors: Calvo Fernández
authors: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, 413 E 69(th) Street, New York, NY 10021, USA.
authors: Rebecca L
authors: RL
authors: Goldstein
authors: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, 413 E 69(th) Street, New York, NY 10021, USA.
authors: Mariano G
authors: MG
authors: Cárdenas
authors: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, 413 E 69(th) Street, New York, NY 10021, USA.
authors: Katerina
authors: K
authors: Hatzi
authors: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, 413 E 69(th) Street, New York, NY 10021, USA.
authors: Monica
authors: M
authors: Rosen
authors: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, 413 E 69(th) Street, New York, NY 10021, USA.
authors: Hao
authors: H
authors: Shen
authors: 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.
authors: Connie M
authors: CM
authors: Corcoran
authors: 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.
authors: Michelle Y
authors: MY
authors: Hamline
authors: 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.
authors: Randy D
authors: RD
authors: Gascoyne
authors: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Ross L
authors: RL
authors: Levine
authors: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors: Omar
authors: O
authors: Abdel-Wahab
authors: Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors: Jonathan D
authors: JD
authors: Licht
authors: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, Cornell University, 413 E 69(th) Street, New York, NY 10021, USA.
authors: Rita
authors: R
authors: Shaknovich
authors: Institute for Computational Biomedicine, Weill Cornell Medical College, Cornell University, New York, NY 10021, USA.
authors: Olivier
authors: O
authors: Elemento
authors: 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.
authors: Vivian J
authors: VJ
authors: Bardwell
authors: 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.
authors: Ari M
authors: AM
authors: Melnick
mesh_terms: D000818:Animals; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000378:metabolism*; D018858:Germinal Center / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D033681:Mitochondrial Membrane Transport Proteins; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D063146:Polycomb-Group Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C084103:BCL6 protein, human; C411984:BCOR protein, human; C490010:Bcl6 protein, mouse; C553467:Bcor protein, mouse; C570428:CBX8 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; C570429:Cbx8 protein, mouse; D063150:Polycomb Repressive Complex 1