title: Crebbploss cooperates withBcl2overexpression to promote lymphoma in mice.
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.
authors.affiliation: 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.|Institute of Biomedical Research of Salamanca, Salamanca, Spain.
authors.forename: Idoia
authors.initials: I
authors.lastname: García-Ramírez
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE.
authors.forename: Saber
authors.initials: S
authors.lastname: Tadros
authors.affiliation: 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.|Institute of Biomedical Research of Salamanca, Salamanca, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: González-Herrero
authors.affiliation: 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.|Institute of Biomedical Research of Salamanca, Salamanca, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Martín-Lorenzo
authors.affiliation: 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.|Institute of Biomedical Research of Salamanca, Salamanca, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Rodríguez-Hernández
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE.
authors.forename: Dalia
authors.initials: D
authors.lastname: Moore
authors.affiliation: 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.|Institute of Biomedical Research of Salamanca, Salamanca, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Ruiz-Roca
authors.affiliation: Institute of Biomedical Research of Salamanca, Salamanca, Spain.|Departamento de Anatomía Patológica, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Blanco
authors.affiliation: Bioinformatics Unit and.
authors.forename: Diego
authors.initials: D
authors.lastname: Alonso-López
authors.affiliation: Institute of Biomedical Research of Salamanca, Salamanca, Spain.|Bioinformatics and Functional Genomics Research Group, Cancer Research Center, Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Salamanca, Spain.
authors.forename: Javier De Las
authors.initials: JL
authors.lastname: Rivas
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE.
authors.forename: Keenan
authors.initials: K
authors.lastname: Hartert
authors.affiliation: Sorbonne Paris Cité, Université Paris Diderot, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Duval
authors.affiliation: Department of Biochemistry and Molecular Biology and.
authors.forename: David
authors.initials: D
authors.lastname: Klinkebiel
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.|Fred and Pamela Buffett Cancer Center, Nebraska Medicine, Omaha, NE.
authors.forename: Martin
authors.initials: M
authors.lastname: Bast
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.|Fred and Pamela Buffett Cancer Center, Nebraska Medicine, Omaha, NE.
authors.forename: Julie
authors.initials: J
authors.lastname: Vose
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE.|Fred and Pamela Buffett Cancer Center, Nebraska Medicine, Omaha, NE.
authors.forename: Matthew
authors.initials: M
authors.lastname: Lunning
authors.affiliation: Fred and Pamela Buffett Cancer Center, Nebraska Medicine, Omaha, NE.|Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.affiliation: Fred and Pamela Buffett Cancer Center, Nebraska Medicine, Omaha, NE.|Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
authors.forename: Timothy
authors.initials: T
authors.lastname: Greiner
authors.affiliation: Sorbonne Paris Cité, Université Paris Diderot, Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, France.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrigues-Lima
authors.affiliation: Institute of Biomedical Research of Salamanca, Salamanca, Spain.|Departamento de Fisiología y Farmacología and.
authors.forename: Rafael
authors.initials: R
authors.lastname: Jiménez
authors.affiliation: Institute of Biomedical Research of Salamanca, Salamanca, Spain.|Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Francisco Javier García
authors.initials: FJG
authors.lastname: Criado
authors.affiliation: Institute of Biomedical Research of Salamanca, Salamanca, Spain.|Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain.
authors.forename: María Begoña García
authors.initials: MBG
authors.lastname: Cenador
authors.affiliation: Department of Biochemistry, St Jude Children's Research Hospital, Memphis, TN.
authors.forename: Paul
authors.initials: P
authors.lastname: Brindle
authors.affiliation: Institute of Biomedical Research of Salamanca, Salamanca, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Vicente-Dueñas
authors.affiliation: Division of Oncology, Department of Medicine, Stanford University, Stanford, CA; and.|Division of Hematology/Oncology, Department of Medicine, Stanford Cancer Institute, Stanford, CA.
authors.forename: Ash
authors.initials: A
authors.lastname: Alizadeh
authors.affiliation: 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.|Institute of Biomedical Research of Salamanca, Salamanca, Spain.
authors.forename: Isidro
authors.initials: I
authors.lastname: Sánchez-García
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE.|Fred and Pamela Buffett Cancer Center, Nebraska Medicine, Omaha, NE.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology*; D050882:CREB-Binding Protein / Q000235:genetics*; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse