Journal
BLOOD
Volume 129, Issue 19, Pages 2645-2656Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-08-733469
Keywords
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Categories
Funding
- Nebraska Department of Health and Human Services [LB506 2016-16]
- National Institutes of Health, National Cancer Institute [1R01CA201380]
- Fondo Europeo de Desarrollo Regional (FEDER)
- Ministry of Economy and Competitiveness [SAF2012-32810, SAF2015-64420-R, SAF2014-57791-REDC]
- Instituto de Salud Carlos III [PIE14/00066]
- Instituto de Salud Carlos III Plan de Ayudas Institute of Biomedical Research of Salamanca Proyectos Integrados [IBY15/00003]
- Junta de Castilla y Leon [BIO/SA51/15, CSI001U14, UIC-017, CSI001U16]
- Fundacion Inocente Inocente
- German Carreras Foundation (Organisation der Deutsche Jose Carreras Leukamie-Stiftung eV) [R13/26]
- Advanced Research on Interaction Mechanisms of electroMagnetic Exposures with Organisms for Risk Assessment project (European Union's Seventh Framework Programme [FP7]) [282891]
- Fred & Pamela Buffett Cancer Center's National Cancer Institute Cancer Center Support Grant [P30CA036727]
- European Union under the FP7 program
- Instituto de Salud Carlos III (Ministerio de Economia y Competitividad) [CP14/00082]
- BES-Ministerio de Economia y Competitividad [BES-2013-063789]
- Fondo Social Europeo-Consejeria de Educacion de la Junta de Castilla y Leon
- Region Ile de France (Appel hors DIM)
- Universite Paris Diderot
- CNRS
- Institut National du Cancer [2012-1-PL-BIO]
- Plan Cancer-Environnement
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CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits in B-cell development and can cooperate with Bcl2 overexpression to promote B-cell lymphoma. Through transcriptional and epigenetic profiling of these B cells, we found that Crebbp inactivation was associated with broad transcriptional alterations, but no changes in the patterns of histone acetylation at the proximal regulatory regions of these genes. However, B cells with Crebbp inactivation showed high expression of Myc and patterns of altered histone acetylation that were localized to intragenic regions, enriched for Myc DNA binding motifs, and showed Myc binding. Through the analysis of CREBBP mutations from a large cohort of primary human FL and DLBCL, we show a significant difference in the spectrum of CREBBP mutations in these 2 diseases, with higher frequencies of nonsense/frameshift mutations in DLBCL compared with FL. Together, our data therefore provide important links between Crebbp inactivation and Bcl2 dependence and show a role for Crebbp inactivation in the induction of Myc expression. We suggest this may parallel the role of CREBBP frameshift/nonsense mutations in DLBCL that result in loss of the protein, but may contrast the role of missense mutations in the lysine acetyltransferase domain that are more frequently observed in FL and yield an inactive protein.
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