Journal
LEUKEMIA
Volume 30, Issue 1, Pages 112-123Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2015.179
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Funding
- 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)
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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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