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Dadun > Depósito Académico > CIMA (Centro de Investigación Médica Aplicada) > Área de Oncología > Oncología molecular > DA - CIMA - Oncología - Oncología molecular - Artículos de Revista >

Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma
Authors: Richter, J.A. (José Ángel)
Robles, E.F. (Eloy Francisco)
Fresquet, V. (Vicente)
Beltran, E. (E.)
Rullan, A.J. (Antonio J.)
Aguirre, X. (Xavier)
Calasanz, M.J. (María José)
Panizo, C. (Carlos)
Richter, J.A. (José Ángel)
Hernandez, J. (J.M.)
Roman-Gomez, J. (José)
Prosper, F. (Felipe)
Martinez-Climent, J.A. (José Angel)
Keywords: Burkitt lymphoma
Cell line tumor
Apoptosis regulatory proteins
Gene expression regulation
Issue Date: 2010
Publisher: American Society of Hematology
Publisher version: http://bloodjournal.hematologylibrary.org/content/116/14/2531
ISSN: 1528-0020
Citation: Richter-Larrea JA, Robles EF, Fresquet V, Beltran E, Rullan AJ, Agirre X, et al. Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma. Blood 2010 Oct 7;116(14):2531-2542.
Abstract
In Burkitt lymphoma/leukemia (BL), achievement of complete remission with first-line chemotherapy remains a challenging issue, as most patients who respond remain disease-free, whereas those refractory have few options of being rescued with salvage therapies. The mechanisms underlying BL chemoresistance and how it can be circumvented remain undetermined. We previously reported the frequent inactivation of the proapoptotic BIM gene in B-cell lymphomas. Here we show that BIM epigenetic silencing by concurrent promoter hypermethylation and deacetylation occurs frequently in primary BL samples and BL-derived cell lines. Remarkably, patients with BL with hypermethylated BIM presented lower complete remission rate (24% vs 79%; P = .002) and shorter overall survival (P = .007) than those with BIM-expressing lymphomas, indicating that BIM transcriptional repression may mediate tumor chemoresistance. Accordingly, by combining in vitro and in vivo studies of human BL-xenografts grown in immunodeficient RAG2(-/-)γc(-/-) mice and of murine B220(+)IgM(+) B-cell lymphomas generated in Eμ-MYC and Eμ-MYC-BIM(+/-) transgenes, we demonstrate that lymphoma chemoresistance is dictated by BIM gene dosage and is reversible on BIM reactivation by genetic manipulation or after treatment with histone-deacetylase inhibitors. We suggest that the combination of histone-deacetylase inhibitors and high-dose chemotherapy may overcome chemoresistance, achieve durable remission, and improve survival of patients with BL.
Permanent link: http://hdl.handle.net/10171/17889
Appears in Collections:DA - CIMA - Oncología - Síndromes mieloproliferativos - Artículos de Revista
DA - CIMA - Oncología - Terapia celular - Artículos de Revista
DA - CIMA - Oncología - Oncología molecular - Artículos de Revista
DA - CUN - Área de Terapia Celular - Artículos de revista
DA - Medicina - Hematología - Artículos de revista

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