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Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients
- Source :
- Leukemia. 30:112-123
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
Abstract
- 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/-XL/-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.
- Subjects :
- 0301 basic medicine
Cancer Research
Stromal cell
CD34
Apoptosis
Biology
Piperazines
Nitrophenols
03 medical and health sciences
0302 clinical medicine
hemic and lymphatic diseases
medicine
Humans
Progenitor cell
Cells, Cultured
Sulfonamides
Stem Cells
Myelodysplastic syndromes
Biphenyl Compounds
Hematology
Bridged Bicyclo Compounds, Heterocyclic
medicine.disease
Biphenyl compound
030104 developmental biology
medicine.anatomical_structure
Proto-Oncogene Proteins c-bcl-2
Oncology
Myelodysplastic Syndromes
030220 oncology & carcinogenesis
Immunology
Myeloid Cell Leukemia Sequence 1 Protein
Bone marrow
Stem cell
Subjects
Details
- ISSN :
- 14765551 and 08876924
- Volume :
- 30
- Database :
- OpenAIRE
- Journal :
- Leukemia
- Accession number :
- edsair.doi.dedup.....30fa8cf1d1d26799e312e53c7bfaefa3