CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas
Yanwen Jiang 1 2 , Ana Ortega-Molina 3 , Huimin Geng 4 , Hsia-Yuan Ying 1 , Katerina Hatzi 1 3 , Sara Parsa 3 , Dylan McNally 1 , Ling Wang 1 , Ashley S Doane 2 , Xabier Agirre 1 5 , Matt Teater 2 , Cem Meydan 2 , Zhuoning Li 1 , David Poloway 1 , Shenqiu Wang 3 , Daisuke Ennishi 6 , David W Scott 6 , Kristy R Stengel 7 , Janice E Kranz 8 , Edward Holson 8 , Sneh Sharma 9 , James W Young 10 , Chi-Shuen Chu 11 , Robert G Roeder 11 , Rita Shaknovich 12 , Scott W Hiebert 7 , Randy D Gascoyne 6 , Wayne Tam 13 , Olivier Elemento 2 , Hans-Guido Wendel 14 , Ari M Melnick 15
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.
CITA DEL ARTÍCULO Cancer Discov. 2017 Jan;7(1):38-53. doi: 10.1158/2159-8290.CD-16-0975. Epub 2016 Oct 12