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Blood. 2017 May 11;129(19):2645-2656. doi: 10.1182/blood-2016-08-733469. Epub 2017 Mar 13.

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice.

Author information

1
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain.
2
Institute of Biomedical Research of Salamanca, Salamanca, Spain.
3
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE.
4
Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain.
5
Bioinformatics Unit and.
6
Bioinformatics and Functional Genomics Research Group, Cancer Research Center, Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Salamanca, Spain.
7
Sorbonne Paris Cité, Université Paris Diderot, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, France.
8
Department of Biochemistry and Molecular Biology and.
9
Division of Hematology/Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.
10
Fred and Pamela Buffett Cancer Center, Nebraska Medicine, Omaha, NE.
11
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
12
Departamento de Fisiología y Farmacología and.
13
Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain.
14
Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN.
15
Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; and.
16
Division of Hematology/Oncology, Department of Medicine, Stanford Cancer Institute, Stanford, CA.

Abstract

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.

PMID:
28288979
PMCID:
PMC5428458
DOI:
10.1182/blood-2016-08-733469
[Indexed for MEDLINE]
Free PMC Article

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