CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas.

Autor:	Jiang Y; 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., Ortega-Molina A; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York., Geng H; Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California., Ying HY; Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York., Hatzi K; 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., Parsa S; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York., McNally D; Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York., Wang L; Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York., Doane AS; Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York., Agirre X; 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., Teater M; Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York., Meydan C; Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York., Li Z; Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York., Poloway D; Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York., Wang S; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York., Ennishi D; Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada., Scott DW; Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada., Stengel KR; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee., Kranz JE; KDAc Therapeutics, Cambridge, Massachusetts., Holson E; KDAc Therapeutics, Cambridge, Massachusetts., Sharma S; Laboratory of Cellular Immunobiology, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York., Young JW; 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., Chu CS; Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York., Roeder RG; Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York., Shaknovich R; Cancer Genetics Incorporated, Rutherford, New Jersey., Hiebert SW; Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee., Gascoyne RD; Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, British Columbia, Canada., Tam W; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York., Elemento O; Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York., Wendel HG; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York. amm2014@med.cornell.edu wendelh@mskcc.org., Melnick AM; Department of Medicine and Weill Cornell Cancer Center, Weill Cornell Medicine, New York, New York. amm2014@med.cornell.edu wendelh@mskcc.org.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2017 Jan; Vol. 7 (1), pp. 38-53. Date of Electronic Publication: 2016 Oct 12.
DOI:	10.1158/2159-8290.CD-16-0975
Abstrakt:	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. Significance: 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. Competing Interests: of Potential Conflicts of Interest: E. Holson is chief scientific officer of KDAc Therapeutics, Inc. No potential conflicts of interest were disclosed by other authors. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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