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Title

Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma

AuthorsRichter-Larrea, Jose A.; Hernández, Jesús M.
Issue Date7-Oct-2010
PublisherAmerican Society of Hematology
CitationBlood 116(14): 2531-2542 (2010)
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.
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.
Publisher version (URL)http://dx.doi.org/10.1182/blood-2010-02-268003
URIhttp://hdl.handle.net/10261/46103
DOI10.1182/blood-2010-02-268003
ISSN0006-4971
Appears in Collections:(IBMCC) Informes y documentos de trabajo
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