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.
Copyright © 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD34 / analysis
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins / physiology
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Bcl-2-Like Protein 11
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Benzamides
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Biphenyl Compounds / pharmacology*
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Cell Line, Tumor / drug effects
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Down-Regulation / drug effects
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Drug Resistance, Neoplasm / drug effects
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Drug Screening Assays, Antitumor
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Drug Synergism
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Gene Expression Regulation, Leukemic / drug effects*
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Hematopoietic Stem Cells / drug effects*
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Hematopoietic Stem Cells / enzymology
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High-Temperature Requirement A Serine Peptidase 2
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Humans
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Imatinib Mesylate
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K562 Cells / drug effects
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
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Membrane Proteins / physiology
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Mitochondrial Proteins / physiology
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / enzymology
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Nitrophenols / pharmacology*
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Piperazines / pharmacology*
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Pyrimidines / pharmacology*
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Serine Endopeptidases / physiology
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Sulfonamides / pharmacology*
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X-Linked Inhibitor of Apoptosis Protein / biosynthesis*
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X-Linked Inhibitor of Apoptosis Protein / genetics
Substances
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ABT-737
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Antigens, CD34
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Benzamides
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Biphenyl Compounds
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Membrane Proteins
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Mitochondrial Proteins
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Neoplasm Proteins
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Nitrophenols
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Piperazines
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Pyrimidines
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Sulfonamides
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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Imatinib Mesylate
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Serine Endopeptidases
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HTRA2 protein, human
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High-Temperature Requirement A Serine Peptidase 2