Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma.
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.
Richter-Larrea
Jose A
JA
Division of Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Robles
Eloy F
EF
Fresquet
Vicente
V
Beltran
Elena
E
Rullan
Antonio J
AJ
Agirre
Xabier
X
Calasanz
Maria José
MJ
Panizo
Carlos
C
Richter
Jose A
JA
Hernandez
Jesus M
JM
Roman-Gomez
Jose
J
Prosper
Felipe
F
Martinez-Climent
Jose A
JA
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D056572:Histone Deacetylase Inhibitors; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D004317:Doxorubicin