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The Hiebert Laboratory

CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas

AUTHORS

Jiang YYanwen , Ortega-Molina AAna , Geng HHuimin , Ying HYHsia-Yuan , Hatzi KKaterina , Parsa SSara , McNally DDylan , Wang LLing , Doane ASAshley S , Agirre XXabier , Teater MMatt , Meydan CCem , Li ZZhuoning , Poloway DDavid , Wang SShenqiu , Ennishi DDaisuke , Scott DWDavid W , Stengel KRKristy R , Kranz JEJanice E , Holson EEdward , Sharma SSneh , Young JWJames W , Chu CSChi-Shuen , Roeder RGRobert G , Shaknovich RRita , Hiebert SWScott W , Gascoyne RDRandy D , Tam WWayne , Elemento OOlivier , Wendel HGHans-Guido , Melnick AMAri M . Cancer discovery. 2016 10 12; 7(1). 38-53

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.

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.