학술논문
CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas
Document Type
article
Author
Jiang, Yanwen; Ortega-Molina, Ana; Geng, Huimin; Ying, Hsia-Yuan; Hatzi, Katerina; Parsa, Sara; McNally, Dylan; Wang, Ling; Doane, Ashley S; Agirre, Xabier; Teater, Matt; Meydan, Cem; Li, Zhuoning; Poloway, David; Wang, Shenqiu; Ennishi, Daisuke; Scott, David W; Stengel, Kristy R; Kranz, Janice E; Holson, Edward; Sharma, Sneh; Young, James W; Chu, Chi-Shuen; Roeder, Robert G; Shaknovich, Rita; Hiebert, Scott W; Gascoyne, Randy D; Tam, Wayne; Elemento, Olivier; Wendel, Hans-Guido; Melnick, Ari M
Source
Cancer Discovery. 7(1)
Subject
Language
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.SignificanceOur 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.