Data from <i>CREBBP</i> Inactivation Promotes the Development of HDAC3-Dependent Lymphomas

Abstract

<div>Abstract<p>Somatic mutations in <i>CREBBP</i> 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 <i>CREBBP</i>-mutant lymphomas <i>in vitro</i> and <i>in vivo</i>. 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 <i>CREBBP</i>-mutant lymphomas.</p><p><b>Significance:</b> Our findings establish the tumor suppressor function of CREBBP in GC lymphomas in which <i>CREBBP</i> 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 <i>CREBBP</i>-mutant lymphomas. <i>Cancer Discov; 7(1); 38–53. ©2016 AACR.</i></p><p><i>See related commentary by Höpken, p. 14</i>.</p><p><i>This article is highlighted in the In This Issue feature, p. 1</i></p></div>