期刊
LEUKEMIA
卷 28, 期 6, 页码 1207-1215出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2014.1
关键词
ABT-199; ABT-737; BCL2; chronic lymphocytic leukaemia; apoptosis; lymphocyte subsets
资金
- Australian National Health and Medical Research Council [461219, 461221, 1051235, 1016701]
- Independent Research Institutes Infrastructure [361646]
- Leukemia and Lymphoma Society [7417-07, 7001-13]
- Australian Research Council
- Leukaemia Foundation of Australia
- Cancer Council of Victoria (Fellowship)
- Australian Cancer Research Foundation
- Victorian State Government Operational Infrastructure Support (OIS) Grant
Overexpression of the prosurvival protein Bcl-2 marks many B-lymphoid malignancies and contributes to resistance to many commonly used chemotherapeutic agents. The first effective BH3 mimetic inhibitors of Bcl-2, ABT-737 and navitoclax, also target Bcl-xL, causing dose-limiting thrombocytopenia. This prompted the development of the Bcl-2-selective antagonist, ABT-199. Here we show that in lymphoid cells, ABT-199 specifically causes Bax/Bak-mediated apoptosis that is triggered principally by the initiator BH3-only protein Bim. As expected, malignant cells isolated from patients with chronic lymphocytic leukaemia are highly sensitive to ABT-199. However, we found that normal, untransformed mature B cells are also highly sensitive to ABT-199, both in vitro and in vivo. By contrast, the B-cell precursors are largely spared, as are cells of myeloid origin. These results pinpoint the probable impact of the pharmacological inhibition of Bcl-2 by ABT-199 on the normal mature haemopoietic cell lineages in patients, and have implications for monitoring during ABT-199 therapy as well as for the clinical utility of this very promising targeted agent.
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