The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors.
BCR-ABL1-specific tyrosine kinase inhibitors prolong the life of patients with chronic myeloid leukemia (CML) but cannot completely eradicate CML progenitors. The BH3 mimetic, ABT-263, targets prosurvival BCL2 family members, and has activity against CML progenitors. However, the inhibitory effect of ABT-263 on BCL-XL, which mediates platelet survival, produces dose-limiting thrombocytopenia. A second-generation BH3 mimetic, ABT-199, has been developed to specifically bind BCL2 but not BCL-XL. We determined the activity of ABT-199 against CML cell lines, as well as primary CML and normal cord blood (NCB) progenitors. We find that BCL2 expression levels predict sensitivity to ABT-199 in CML and NCB progenitors, and that high NCB BCL2 levels may explain the reported hematologic toxicities in ABT-199-treated patients. Also, while single agent ABT-199 has modest activity against CML progenitors, when combined with imatinib, ABT-199 significantly enhances imatinib activity against CML progenitors at concentrations predicted to avoid hematologic toxicities.
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- Tumor Stem Cell Assay
- Sulfonamides
- Pyrimidines
- Proto-Oncogene Proteins c-bcl-2
- Protein Kinase Inhibitors
- Piperazines
- Neoplastic Stem Cells
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- Imatinib Mesylate
- Humans
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Tumor Stem Cell Assay
- Sulfonamides
- Pyrimidines
- Proto-Oncogene Proteins c-bcl-2
- Protein Kinase Inhibitors
- Piperazines
- Neoplastic Stem Cells
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- Imatinib Mesylate
- Humans