title: The CREBBP Acetyltransferase Is a Haploinsufficient Tumor Suppressor in B-cell Lymphoma.
abstract: Inactivating mutations of the CREBBP acetyltransferase are highly frequent in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the two most common germinal center (GC)-derived cancers. However, the role of CREBBP inactivation in lymphomagenesis remains unclear. Here, we show that CREBBP regulates enhancer/super-enhancer networks with central roles in GC/post-GC cell fate decisions, including genes involved in signal transduction by the B-cell receptor and CD40 receptor, transcriptional control of GC and plasma cell development, and antigen presentation. Consistently,Crebbp-deficient B cells exhibit enhanced response to mitogenic stimuli and perturbed plasma cell differentiation. Although GC-specific loss ofCrebbpwas insufficient to initiate malignant transformation, compoundCrebbp-haploinsufficient/BCL2-transgenic mice, mimicking the genetics of FL and DLBCL, develop clonal lymphomas recapitulating the features of the human diseases. These findings establishCREBBPas a haploinsufficient tumor-suppressor gene in GC B cells and provide insights into the mechanisms by which its loss contributes to lymphomagenesis.Significance:Loss-of-function mutations ofCREBBPare common and early lesions in FL and DLBCL, suggesting a prominent role in lymphoma initiation. Our studies identify the cellular program by which reduced CREBBP dosage facilitates malignant transformation, and have direct implications for targeted lymphoma therapy based on drugs affecting CREBBP-mediated chromatin acetylation.Cancer Discov; 7(3); 322-37. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 235.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York.
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York.
authors.forename: Sofija
authors.initials: S
authors.lastname: Vlasevska
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Wells
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York.
authors.forename: Sarah
authors.initials: S
authors.lastname: Nataraj
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York.
authors.forename: Antony B
authors.initials: AB
authors.lastname: Holmes
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York.
authors.forename: Romain
authors.initials: R
authors.lastname: Duval
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York.
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Meyer
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York.
authors.forename: Tongwei
authors.initials: T
authors.lastname: Mo
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York.|Department of Pathology and Cell Biology, Columbia University, New York, New York.
authors.forename: Katia
authors.initials: K
authors.lastname: Basso
authors.affiliation: Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Brindle
authors.affiliation: Department of Pathology and Laboratory Medicine, NorthWell Health, Staten Island University Hospital, Staten Island, New York.
authors.forename: Shafinaz
authors.initials: S
authors.lastname: Hussein
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York.|Department of Pathology and Cell Biology, Columbia University, New York, New York.|Department of Genetics and Development, Columbia University, New York, New York.|Department of Microbiology and Immunology, Columbia University, New York, New York.|Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York. lp171@cumc.columbia.edu.|Department of Pathology and Cell Biology, Columbia University, New York, New York.|Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D050882:CREB-Binding Protein / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D018858:Germinal Center / Q000473:pathology; D057895:Haploinsufficiency; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010950:Plasma Cells / Q000187:drug effects / Q000473:pathology; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000378:metabolism
chemical_list: C084103:BCL6 protein, human; D002843:Chromatin; D051560:Proto-Oncogene Proteins c-bcl-6; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; C494364:Crebbp protein, mouse