期刊
LEUKEMIA
卷 30, 期 1, 页码 112-123出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2015.179
关键词
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资金
- Max Eder Program grant from the Deutsche Krebshilfe [111738]
- Human Frontiers Science Program grant [kiRGY0073/2012]
- German Jose Carreras Leukemia Foundation [DJCLS R 12/22, DJCLS R 11/12]
- Dcutschc Forschungsgemeinschaft [Forschergruppe FOR2036]
- Novartis
- German Research Foundation (DFG) [00 8/5, 00 8/9, FOR 2033]
- German Research Foundation [Go 713/2-1]
- Deutsche Konsortium fur Translationale Krcbsforschung (DKTK) of the German Cancer Center (DKFZ)
Deregulated apoptosis is an identifying feature of myelodysplastic syndromes (MDS). Whereas apoptosis is increased in the bone marrow (BM) of low-risk MDS patients, progression to high-risk MDS correlates with an acquired resistance to apoptosis and an aberrant expression of BCL-2 proteins. To overcome the acquired apoptotic resistance in high-risk MDS, we investigated the induction of apoptosis by inhibition of pro-survival BCL-2 proteins using the BCL-2/-X-L/-W inhibitor ABT-737 or the BCL-2-selective inhibitor ABT-199. We characterized a cohort of 124 primary human BM samples from MDS/secondary acute myeloid leukemia (sAML) patients and 57 healthy, age-matched controls. Inhibition of anti-apoptotic BCL-2 proteins was specifically toxic for BM cells from high-risk MDS and sAML patients, whereas low-risk MDS or healthy controls remained unaffected. Notably, ABT-737 or ABT-199 treatment was capable of targeting the MDS stem/progenitor compartment in high-risk MDS/sAML samples as shown by the reduction in CD34(+) cells and the decreased colony-forming capacity. Elevated expression of MCL-1 conveyed resistance against both compounds. Protection by stromal cells only partially inhibited induction of apoptosis. Collectively, our data show that the apoptotic resistance observed in high-risk MDS/sAML cells can be overcome by the ABT-737 or ABT-199 treatment and implies that BH3 mimetics might delay disease progression in higher-risk MDS or sAML patients.
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