| First Author | Jiang Y | Year | 2017 |
| Journal | Cancer Discov | Volume | 7 |
| Issue | 1 | Pages | 38-53 |
| PubMed ID | 27733359 | Mgi Jnum | J:237941 |
| Mgi Id | MGI:5817540 | Doi | 10.1158/2159-8290.CD-16-0975 |
| Citation | Jiang Y, et al. (2017) CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas. Cancer Discov 7(1):38-53 |
| abstractText | 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. (c)2016 AACR.See related commentary by Hopken, p. 14This article is highlighted in the In This Issue feature, p. 1. |
