CREBBP inactivation promotes the development of HDAC3-dependent lymphomas Journal Article
| Authors: | 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.; Holson, E.; Sharma, S.; Young, J. W.; Chu, C. S.; Roeder, R. G.; Shaknovich, R.; Hiebert, S. W.; Gascoyne, R. D.; Tam, W.; Elemento, O.; Wendel, H. G.; Melnick, A. M. |
| Article Title: | CREBBP inactivation promotes the development of HDAC3-dependent lymphomas |
| 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. © 2017 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 7 |
| Issue: | 1 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2017-01-01 |
| Start Page: | 38 |
| End Page: | 53 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-16-0975 |
| PROVIDER: | scopus |
| PUBMED: | 27733359 |
| PMCID: | PMC5300005 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 February 2017 -- Source: Scopus |
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