Format

Send to

Choose Destination
Oncotarget. 2014 Oct 15;5(19):9033-8.

The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors.

Author information

1
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore.
2
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore. Department of Haematology, Singapore General Hospital, Singapore.
3
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore. Department of Haematology, Singapore General Hospital, Singapore. Department of Medical Oncology, National Cancer Centre, Singapore. Department of Medicine, Duke University Medical Center, Durham, NC.

Abstract

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.

PMID:
25333252
PMCID:
PMC4253416
DOI:
10.18632/oncotarget.1925
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Impact Journals, LLC Icon for PubMed Central
Loading ...
Support Center