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

// Tun Kiat Ko 1 , Charles T.H. Chuah 1,2 , John W.J. Huang 1 , King-Pan Ng 1 and S. Tiong Ong 1,2,3,4 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 Correspondence: 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 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-X L , 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-X L . 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.