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

Research output: Contribution to journalArticle

72 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

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Lymphoma
Acetylation
Germinal Center
B-Lymphocytes
MHC Class II Genes
Mutation
Gene Silencing
B-Cell Lymphoma
Histones
Therapeutics
Genes
Neoplasms

ASJC Scopus subject areas

  • Oncology

Cite this

Jiang, Y., Ortega-Molina, A., Geng, H., Ying, H. Y., Hatzi, K., Parsa, S., ... 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

CREBBP inactivation promotes the development of HDAC3-dependent lymphomas. / Jiang, Yanwen; Ortega-Molina, Ana; Geng, Huimin; Ying, Hsia Yuan; Hatzi, Katerina; Parsa, Sara; McNally, Dylan; Wang, Ling; Doane, Ashley S.; Agirre, Xabier; Teater, Matt; Meydan, Cem; Li, Zhuoning; Poloway, David; Wang, Shenqiu; Ennishi, Daisuke; Scott, David W.; Stengel, Kristy R.; Kranz, Janice E.; Holson, Edward; Sharma, Sneh; Young, James W.; Chu, Chi Shuen; Roeder, Robert G.; Shaknovich, Rita; Hiebert, Scott W.; Gascoyne, Randy D.; Tam, Wayne; Elemento, Olivier; Wendel, Hans Guido; Melnick, Ari M.

In: Cancer Discovery, Vol. 7, No. 1, 01.01.2017, p. 38-53.

Research output: Contribution to journalArticle

Jiang, Y, Ortega-Molina, A, Geng, H, Ying, HY, Hatzi, K, Parsa, S, McNally, D, Wang, L, Doane, AS, Agirre, X, Teater, M, Meydan, C, Li, Z, Poloway, D, Wang, S, Ennishi, D, Scott, DW, Stengel, KR, Kranz, JE, Holson, E, Sharma, S, Young, JW, Chu, CS, Roeder, RG, Shaknovich, R, Hiebert, SW, Gascoyne, RD, Tam, W, Elemento, O, Wendel, HG & Melnick, AM 2017, 'CREBBP inactivation promotes the development of HDAC3-dependent lymphomas', Cancer Discovery, vol. 7, no. 1, pp. 38-53. https://doi.org/10.1158/2159-8290.CD-16-0975
Jiang Y, Ortega-Molina A, Geng H, Ying HY, Hatzi K, Parsa S et al. CREBBP inactivation promotes the development of HDAC3-dependent lymphomas. Cancer Discovery. 2017 Jan 1;7(1):38-53. https://doi.org/10.1158/2159-8290.CD-16-0975
Jiang, Yanwen ; Ortega-Molina, Ana ; Geng, Huimin ; Ying, Hsia Yuan ; Hatzi, Katerina ; Parsa, Sara ; McNally, Dylan ; Wang, Ling ; Doane, Ashley S. ; Agirre, Xabier ; Teater, Matt ; Meydan, Cem ; Li, Zhuoning ; Poloway, David ; Wang, Shenqiu ; Ennishi, Daisuke ; Scott, David W. ; Stengel, Kristy R. ; Kranz, Janice E. ; Holson, Edward ; Sharma, Sneh ; Young, James W. ; Chu, Chi Shuen ; Roeder, Robert G. ; Shaknovich, Rita ; Hiebert, Scott W. ; Gascoyne, Randy D. ; Tam, Wayne ; Elemento, Olivier ; Wendel, Hans Guido ; Melnick, Ari M. / CREBBP inactivation promotes the development of HDAC3-dependent lymphomas. In: Cancer Discovery. 2017 ; Vol. 7, No. 1. pp. 38-53.
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T1 - CREBBP inactivation promotes the development of HDAC3-dependent lymphomas

AU - Jiang, Yanwen

AU - Ortega-Molina, Ana

AU - Geng, Huimin

AU - Ying, Hsia Yuan

AU - Hatzi, Katerina

AU - Parsa, Sara

AU - McNally, Dylan

AU - Wang, Ling

AU - Doane, Ashley S.

AU - Agirre, Xabier

AU - Teater, Matt

AU - Meydan, Cem

AU - Li, Zhuoning

AU - Poloway, David

AU - Wang, Shenqiu

AU - Ennishi, Daisuke

AU - Scott, David W.

AU - Stengel, Kristy R.

AU - Kranz, Janice E.

AU - Holson, Edward

AU - Sharma, Sneh

AU - Young, James W.

AU - Chu, Chi Shuen

AU - Roeder, Robert G.

AU - Shaknovich, Rita

AU - Hiebert, Scott W.

AU - Gascoyne, Randy D.

AU - Tam, Wayne

AU - Elemento, Olivier

AU - Wendel, Hans Guido

AU - Melnick, Ari M.

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N2 - 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.

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