biostudies-literatureJiang YNCI NIH HHS38-53https://www.ebi.ac.uk/biostudies/studies/S-EPMC5300005biostudies-literatureUnknown7(1)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 vivCancer discoveryCREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas.PMC5300005R01 CA164605R01 CA187109R01 CA190384P01 CA023766P30 CA008748R01 CA183876R01 CA194547R01 CA178765T32 CA009582P50 CA192937Melnick AMDoane ASChu CSEnnishi DRoeder RGMcNally DTeater MHolson EWang LJiang YOrtega-Molina AWang SScott DWGascoyne RDYing HYKranz JEWendel HGSharma SElemento OMeydan CAgirre XLi ZGeng HYoung JWParsa SHatzi KStengel KRTam WPoloway DShaknovich RHiebert SWfalseCREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas.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 viv2017-01-01T00:00:00Z2017 Jan2026-04-17T15:23:39.501Z2019-03-27T02:36:11ZS-EPMC53000052773335910.1158/2159-8290.CD-16-097510.1158/2159-8290.cd-16-0975