Maximal killing of lymphoma cells by DNA damage-inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim
Details
Publication Year 2010-12-09, Volume 116, Issue #24, Page 5256-5267
Journal Title
BLOOD
Publication Type
Journal Article
Abstract
DNA-damaging chemotherapy is the backbone of cancer treatment, although it is not clear how such treatments kill tumor cells. In nontransformed lymphoid cells, the combined loss of 2 proapoptotic p53 target genes, Puma and Noxa, induces as much resistance to DNA damage as loss of p53 itself. In E mu-Myc lymphomas, however, lack of both Puma and Noxa resulted in no greater drug resistance than lack of Puma alone. A third B-cell lymphoma-2 homology domain (BH)3-only gene, Bim, although not a direct p53 target, was up-regulated in E mu-Myc lymphomas incurring DNA damage, and knockdown of Bim levels markedly increased the drug resistance of E mu-Myc/Puma(-/-)Noxa(-/-) lymphomas both in vitro and in vivo. Remarkably, c-MYC-driven lymphoma cell lines from Noxa(-/-)Puma(-/-)Bim(-/-) mice were as resistant as those lacking p53. Thus, the combinatorial action of Puma, Noxa, and Bim is critical for optimal apoptotic responses of lymphoma cells to 2 commonly used DNA-damaging chemotherapeutic agents, identifying Bim as an additional biomarker for treatment outcome in the clinic. (Blood. 2010;116(24):5256-5267)
Publisher
AMER SOC HEMATOLOGY
Keywords
MYC-INDUCED LYMPHOMAGENESIS; FOXO TRANSCRIPTION FACTORS; BH3-ONLY PROTEINS PUMA; BCL-2 PROTEINS; APOPTOTIC RESPONSES; TRIGGERS APOPTOSIS; TRANSGENIC MICE; IN-VIVO; B-CELLS; C-MYC
WEHI Research Division(s)
Molecular Genetics Of Cancer; Bioinformatics
Rights Notice
© 2010 by The American Society of Hematology


Creation Date: 2010-12-09 12:00:00
Last Modified: 0001-01-01 12:00:00
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