CREBBP inactivation promotes the development of HDAC3-dependent lymphomas

Yanwen Jiang, Ana Ortega-Molina, Huimin Geng, Hsia Yuan Ying, Katerina Hatzi, Sara Parsa, Dylan McNally, Ling Wang, Ashley S. Doane, Xabier Agirre, Matt Teater, Cem Meydan, Zhuoning Li, David Poloway, Shenqiu Wang, Daisuke Ennishi, David W. Scott, Kristy R. Stengel, Janice E. Kranz, Edward HolsonSneh Sharma, James W. Young, Chi Shuen Chu, Robert G. Roeder, Rita Shaknovich, Scott W. Hiebert, Randy D. Gascoyne, Wayne Tam, Olivier Elemento, Hans Guido Wendel, Ari M. Melnick

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88 Citations (Scopus)

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 fi ndings 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.

Original languageEnglish
Pages (from-to)38-53
Number of pages16
JournalCancer Discovery
Volume7
Issue number1
DOIs
Publication statusPublished - Jan 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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    Jiang, Y., Ortega-Molina, A., Geng, H., Ying, H. Y., Hatzi, K., Parsa, S., McNally, D., Wang, L., Doane, A. S., Agirre, X., Teater, M., Meydan, C., Li, Z., Poloway, D., Wang, S., Ennishi, D., Scott, D. W., Stengel, K. R., Kranz, J. E., ... Melnick, A. M. (2017). CREBBP inactivation promotes the development of HDAC3-dependent lymphomas. Cancer Discovery, 7(1), 38-53. https://doi.org/10.1158/2159-8290.CD-16-0975