Scientific publications

CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas

Jan 1, 2017 | Magazine: Cancer Discovery

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

Our authors