title: CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas.
abstract: Somatic mutations in CREBBP occur frequently in B-cell lymphoma. Here, we show that loss of CREBBP facilitates the development of germinal center (GC)-derived lymphomas in mice. In both human and murine lymphomas, CREBBP loss-of-function resulted in focal depletion of enhancer H3K27 acetylation and aberrant transcriptional silencing of genes that regulate B-cell signaling and immune responses, including class II MHC. Mechanistically, CREBBP-regulated enhancers are counter-regulated by the BCL6 transcriptional repressor in a complex with SMRT and HDAC3, which we found to bind extensively to MHC class II loci. HDAC3 loss-of-function rescued repression of these enhancers and corresponding genes, including MHC class II, and more profoundly suppressed CREBBP-mutant lymphomas in vitro and in vivo Hence, CREBBP loss-of-function contributes to lymphomagenesis by enabling unopposed suppression of enhancers by BCL6/SMRT/HDAC3 complexes, suggesting HDAC3-targeted therapy as a precision approach for CREBBP-mutant lymphomas.
  
  
  
  Our findings establish the tumor suppressor function of CREBBP in GC lymphomas in which CREBBP mutations disable acetylation and result in unopposed deacetylation by BCL6/SMRT/HDAC3 complexes at enhancers of B-cell signaling and immune response genes. Hence, inhibition of HDAC3 can restore the enhancer histone acetylation and may serve as a targeted therapy for CREBBP-mutant lymphomas. Cancer Discov; 7(1); 38-53. ©2016 AACR.See related commentary by Höpken, p. 14This article is highlighted in the In This Issue feature, p. 1.
authors.affiliation: Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York.|Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ana
authors.initials: A
authors.lastname: Ortega-Molina
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.affiliation: Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York.
authors.forename: Hsia-Yuan
authors.initials: HY
authors.lastname: Ying
authors.affiliation: Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York.|Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Katerina
authors.initials: K
authors.lastname: Hatzi
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sara
authors.initials: S
authors.lastname: Parsa
authors.affiliation: Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York.
authors.forename: Dylan
authors.initials: D
authors.lastname: McNally
authors.affiliation: Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Doane
authors.affiliation: Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York.|Area de Oncología, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain.
authors.forename: Xabier
authors.initials: X
authors.lastname: Agirre
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Matt
authors.initials: M
authors.lastname: Teater
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Cem
authors.initials: C
authors.lastname: Meydan
authors.affiliation: Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York.
authors.forename: Zhuoning
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York.
authors.forename: David
authors.initials: D
authors.lastname: Poloway
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Shenqiu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ennishi
authors.affiliation: Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Kristy R
authors.initials: KR
authors.lastname: Stengel
authors.affiliation: KDAc Therapeutics, Cambridge, Massachusetts.
authors.forename: Janice E
authors.initials: JE
authors.lastname: Kranz
authors.affiliation: KDAc Therapeutics, Cambridge, Massachusetts.
authors.forename: Edward
authors.initials: E
authors.lastname: Holson
authors.affiliation: Laboratory of Cellular Immunobiology, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sneh
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Laboratory of Cellular Immunobiology, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine; The Rockefeller University, New York, New York.
authors.forename: James W
authors.initials: JW
authors.lastname: Young
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York.
authors.forename: Chi-Shuen
authors.initials: CS
authors.lastname: Chu
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.affiliation: Cancer Genetics Incorporated, Rutherford, New Jersey.
authors.forename: Rita
authors.initials: R
authors.lastname: Shaknovich
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Hiebert
authors.affiliation: Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.
authors.forename: Wayne
authors.initials: W
authors.lastname: Tam
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York. amm2014@med.cornell.edu wendelh@mskcc.org.
authors.forename: Hans-Guido
authors.initials: HG
authors.lastname: Wendel
authors.affiliation: Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York. amm2014@med.cornell.edu wendelh@mskcc.org.
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
mesh_terms: D000107:Acetylation; D000818:Animals; D050882:CREB-Binding Protein / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004742:Enhancer Elements, Genetic; D055786:Gene Knockout Techniques; D018858:Germinal Center / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics; D014158:Transcription, Genetic; D000099186:Histone Deacetylase 3
chemical_list: D050882:CREB-Binding Protein; D006655:Histone Deacetylases; D006657:Histones; D056985:Nuclear Receptor Co-Repressor 2; D051560:Proto-Oncogene Proteins c-bcl-6; D000099186:Histone Deacetylase 3; C084103:BCL6 protein, human; C539130:NCOR2 protein, human; C494363:CREBBP protein, human