title: ABT-737 increases tyrosine kinase inhibitor-induced apoptosis in chronic myeloid leukemia cells through XIAP downregulation and sensitizes CD34(+) CD38(-) population to imatinib.
abstract: Chronic myeloid leukemia (CML) tumorigenicity is driven by the oncogenic BCR-ABL tyrosine kinase. Specific tyrosine kinase inhibitors (TKI) have been designed and are now used for the treatment of CML. These TKI induce apoptosis in leukemic cells in a BIM-dependent mechanism. We hypothesized that an increase in BIM activity could sensitize CML cells to TKI. We blocked the anti-apoptotic proteins of the Bcl-2 family by using ABT-737, a Bcl-2 and Bcl-XL inhibitor. ABT-737 modified Bcl-2 protein interactions toward a pro-apoptotic phenotype. Its combination with TKI resulted in a strong synergism in CML cell lines. The association also induced a large decrease in X-linked inhibitor of apoptosis (XIAP), followed by caspase-3 activation. This XIAP decrease was due to post-translational events. The mitochondrial serine protease HtrA2/Omi was identified as being responsible for this off-target effect. Then, ABT-737 and TKI cooperate at several levels to induce apoptosis of CML cells lines, and the benefit of this association was also observed in CML hematopoietic progenitors. Interestingly, a lethal effect was also observed in the more immature CD34(+)CD38(-) TKI-insensitive population. Combination therapy might by an interesting strategy for the treatment of CML patients.
authors.affiliation: Laboratoire d'Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM 1035, Université Bordeaux Segalen, Bordeaux Cedex, France. kelly.airiau@gmail.com
authors.forename: Kelly
authors.initials: K
authors.lastname: Airiau
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Mahon
authors.forename: Marina
authors.initials: M
authors.lastname: Josselin
authors.forename: Marie
authors.initials: M
authors.lastname: Jeanneteau
authors.forename: Beatrice
authors.initials: B
authors.lastname: Turcq
authors.forename: Francis
authors.initials: F
authors.lastname: Belloc
mesh_terms: D018952:Antigens, CD34 / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D001549:Benzamides; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000201:enzymology; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells / Q000187:drug effects; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D008565:Membrane Proteins / Q000502:physiology; D024101:Mitochondrial Proteins / Q000502:physiology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C501332:ABT-737; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D001549:Benzamides; D001713:Biphenyl Compounds; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D009596:Nitrophenols; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D013449:Sulfonamides; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000068877:Imatinib Mesylate; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2