CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas

作者：Yanwen Jiang, Ana Ortega-Molina, Huimin Geng, Hsia‐Yuan Ying, Katerina Hatzi, Sara Parsa, Dylan R. McNally, Ling Wang, Ashley S. Doane, Xabier Agirre, Matt R. Teater, Cem Meydan, Zhuoning Li, David Poloway, Shenqiu Wang, Daisuke Ennishi, David W. Scott, Kristy R. Stengel, Janice E. Kranz, Edward B. Holson, Sneh Sharma, James W. Young, Chi-Shuen Chu, Robert G. Roeder, Rita Shaknovich, Scott W. Hiebert, Randy D. Gascoyne, Wayne Tam, Olivier Elemento, Hans‐Guido Wendel, Ari M. Melnick · 发表于：Cancer Discovery · 年份：2016 · DOI：10.1158/2159-8290.cd-16-0975 · 被引用次数：280 · 研究领域：Histone Deacetylase Inhibitors Research、Lymphoma Diagnosis and Treatment、Cancer Immunotherapy and Biomarkers

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 Höpk...