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dc.contributor.authorRichter-Larrea, Jose A.-
dc.contributor.authorHernández, Jesús M.-
dc.identifier.citationBlood 116(14): 2531-2542 (2010)es_ES
dc.descriptionPresented in part as an oral communication at the 50th annual meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2008.-- El pdf del artículo es la versión post-print.-- et al.es_ES
dc.description.abstractIn 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.es_ES
dc.description.sponsorshipThis work was supported by the Spanish Ministry of Science and Innovation (grants PI081878 and RTICC-RD06/0020-0088/ 0111/0066/0006)-FEDER, the Navarra Government (Education and Health Councils), the Cooperación de Investigación Transpirenaica en la Terapia Innovadora de la Leucemia (CITTIL) Spanish-French EU Program, and the UTE-Center for Applied Medical Research project. J.A.R.-L. and E.B. are supported by predoctoral fellowships from the Spanish Ministry of Science and Innovation.es_ES
dc.publisherAmerican Society of Hematologyes_ES
dc.titleReversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphomaes_ES
dc.description.peerreviewedPeer reviewedes_ES
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