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CREBBP Inactivation promotes the development of HDAC3-Dependent Lymphomas

Autores: Jiang, Y.; Ortega-Molina, A.; Geng, H. M.; Ying, H. Y. ; Hatzi, K. ; Parsa, S. ; McNally, D. ; Wang, L. ; Doane, A. S. ; Aguirre Ena, Xabier; Teater, M.; Meydan, C.; Li, Z. N. ; Poloway, D. ; Wang, S. Q. ; 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.
Título de la revista: CANCER DISCOVERY
ISSN: 2159-8274
Volumen: 7
Número: 1
Páginas: 38 - 53
Fecha de publicación: 2017
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. (C) 2016 AACR.