Research Papers:

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

Tun Kiat Ko, Charles T.H. Chuah, John W.J. Huang, King-Pan Ng and S. Tiong Ong _

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Oncotarget. 2014; 5:9033-9038. https://doi.org/10.18632/oncotarget.1925

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Tun Kiat Ko1, Charles T.H. Chuah1,2, John W.J. Huang1 , King-Pan Ng1 and S. Tiong Ong1,2,3,4

1 Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore

2 Department of Haematology, Singapore General Hospital, Singapore

3 Department of Medical Oncology, National Cancer Centre, Singapore

4 Department of Medicine, Duke University Medical Center, Durham, NC


S. Tiong Ong, email:

Keywords: ABT-199, BH3 mimetic, imatinib, CML, normal cord blood, progenitors

Received: March 14, 2014 Accepted: April 25, 2014 Published: April 27, 2014


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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