Maximal killing of lymphoma cells by DNA damage-inducing therapy requires not only the p53 targets Puma and Noxa, but also Bim
- Author(s)
- Happo, L; Cragg, MS; Phipson, B; Haga, JM; Jansen, ES; Herold, MJ; Dewson, G; Michalak, EM; Vandenberg, CJ; Smyth, GK; Strasser, A; Cory, S; Scott, CL;
- 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
- Research Division(s)
- Molecular Genetics Of Cancer; Bioinformatics
- Publisher's Version
- https://doi.org/10.1182/blood-2010-04-280818
- Open Access at Publisher's Site
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- © 2010 by The American Society of Hematology
Creation Date: 2010-12-09 12:00:00