The CREBBP Acetyltransferase Is a Haploinsufficient Tumor Suppressor in B-cell Lymphoma.

Autor:	Zhang J; Institute for Cancer Genetics, Columbia University, New York, New York., Vlasevska S; Institute for Cancer Genetics, Columbia University, New York, New York., Wells VA; Institute for Cancer Genetics, Columbia University, New York, New York., Nataraj S; Institute for Cancer Genetics, Columbia University, New York, New York., Holmes AB; Institute for Cancer Genetics, Columbia University, New York, New York., Duval R; Institute for Cancer Genetics, Columbia University, New York, New York., Meyer SN; Institute for Cancer Genetics, Columbia University, New York, New York., Mo T; Institute for Cancer Genetics, Columbia University, New York, New York., Basso K; Institute for Cancer Genetics, Columbia University, New York, New York.; Department of Pathology and Cell Biology, Columbia University, New York, New York., Brindle PK; Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee., Hussein S; Department of Pathology and Laboratory Medicine, NorthWell Health, Staten Island University Hospital, Staten Island, New York., Dalla-Favera R; 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., Pasqualucci L; 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.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2017 Mar; Vol. 7 (3), pp. 322-337. Date of Electronic Publication: 2017 Jan 09.
DOI:	10.1158/2159-8290.CD-16-1417
Abstrakt:	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 of Crebbp was insufficient to initiate malignant transformation, compound Crebbp -haploinsufficient/BCL2-transgenic mice, mimicking the genetics of FL and DLBCL, develop clonal lymphomas recapitulating the features of the human diseases. These findings establish CREBBP as 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 of CREBBP are 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 . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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