title: The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors.
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.
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Tun Kiat
authors.initials: TK
authors.lastname: Ko
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore. Department of Haematology, Singapore General Hospital, Singapore.
authors.forename: Charles T H
authors.initials: CT
authors.lastname: Chuah
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore.
authors.forename: John W J
authors.initials: JW
authors.lastname: Huang
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore.
authors.forename: King-Pan
authors.initials: KP
authors.lastname: Ng
authors.affiliation: 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.
authors.forename: S Tiong
authors.initials: ST
authors.lastname: Ong
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D013449:Sulfonamides; D000068877:Imatinib Mesylate; C579720:venetoclax; C528561:navitoclax