CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas. Academic Article uri icon

Overview

abstract

  • UNLABELLED: 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.

publication date

  • October 12, 2016

Research

keywords

  • CREB-Binding Protein
  • Germinal Center
  • Histone Deacetylases
  • Lymphoma, Large B-Cell, Diffuse
  • Mutation

Identity

PubMed Central ID

  • PMC5300005

Scopus Document Identifier

  • 85009410568

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-16-0975

PubMed ID

  • 27733359

Additional Document Info

volume

  • 7

issue

  • 1