CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas

Authors

Jiang Y Yanwen , Ortega-Molina A Ana , Geng H Huimin , Ying HY Hsia-Yuan , Hatzi K Katerina , Parsa S Sara , McNally D Dylan , Wang L Ling , Doane AS Ashley S , Agirre X Xabier , Teater M Matt , Meydan C Cem , Li Z Zhuoning , Poloway D David , Wang S Shenqiu , Ennishi D Daisuke , Scott DW David W , Stengel KR Kristy R , Kranz JE Janice E , Holson E Edward , Sharma S Sneh , Young JW James W , Chu CS Chi-Shuen , Roeder RG Robert G , Shaknovich R Rita , Hiebert SW Scott W , Gascoyne RD Randy D , Tam W Wayne , Elemento O Olivier , Wendel HG Hans-Guido , Melnick AM Ari 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.