期刊
BLOOD
卷 116, 期 24, 页码 5256-5267出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-04-280818
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资金
- National Health and Medical Research Council (Australia) [257502, CDA 406675]
- Leukemia and Lymphoma Society (New York) [7015, 3209-04]
- National Cancer Institute (National Institutes of Health) [CA 80188, CA 43540]
- Leukemia and Lymphoma Research UK
- DFG (German Science Foundation)
- Leukemia Foundation Australia
- University of Melbourne
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)
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