CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas
| Autor: | Dylan R. McNally, Robert G. Roeder, Ling Wang, David W. Scott, Zhuoning Li, Janice E. Kranz, Cem Meydan, Edward B. Holson, Olivier Elemento, Ashley S. Doane, Yanwen Jiang, Wayne Tam, Xabier Agirre, Randy D. Gascoyne, Ari Melnick, James W. Young, Kristy R. Stengel, Daisuke Ennishi, Sneh Sharma, Hsia-Yuan Ying, Shenqiu Wang, Ana Ortega-Molina, Scott W. Hiebert, Katerina Hatzi, Huimin Geng, David Poloway, Sara Parsa, Matt Teater, Hans-Guido Wendel, Chi-Shuen Chu, Rita Shaknovich |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Transcription Genetic Lymphoma Histones Mice Gene Knockout Techniques 0302 clinical medicine immune system diseases hemic and lymphatic diseases 2.1 Biological and endogenous factors Aetiology Nuclear receptor co-repressor 2 Cancer Tumor Acetylation Hematology BCL6 CREB-Binding Protein Diffuse Cell biology Enhancer Elements Genetic Oncology 030220 oncology & carcinogenesis Proto-Oncogene Proteins c-bcl-6 Lymphoma Large B-Cell Diffuse Transcription Biotechnology Enhancer Elements Oncology and Carcinogenesis Biology Histone Deacetylases Cell Line 03 medical and health sciences Rare Diseases Genetic Clinical Research Cell Line Tumor Large B-Cell Genetics Gene silencing Animals Humans Nuclear Receptor Co-Repressor 2 CREB-binding protein Enhancer Loss function Germinal center HDAC3 Germinal Center Molecular biology 030104 developmental biology Mutation biology.protein Neoplasm Transplantation |
| Zdroj: | Cancer discovery, vol 7, iss 1 |
| Popis: | 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. 14. This article is highlighted in the In This Issue feature, p. 1 |
| Databáze: | OpenAIRE |
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