Implicación de bim en la resistencia terapéutica del linfoma de burkitt

Abstract

In Burkitt lymphoma/leukemia (BL), achievement of complete remission (CR) 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 pro-apoptotic 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=0.002) and shorter overall survival (p=0.007) 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 BLxenografts grown in immunodeficient RAG2-/-IL2gammac-/- mice and of murine B220+IgM+ B-cell lymphomas generated in Emu-MYC and Emu-MYC-BIM+/- transgenes, we demonstrate that lymphoma chemoresistance is dictated by BIM gene dosage and is reversible upon BIM reactivation by genetic manipulation or after treatment with histone-deacetylase inhibitors (HDACis). We suggest that the combination of HDACis and high-dose chemotherapy may overcome chemoresistance, achieve durable remission and improve survival of patients with BL.