Abstract
Identification of signaling pathways downstream of Abl tyrosine kinase may increase our understanding of the pathogenesis of chronic myelogenous leukemia (CML) and suggest strategies to improve clinical treatment of the disease. By combining the use of a phosphospecific antibody recognizing a substrate motif of serine/threonine kinases with bioinformatics, we found that the translational regulators ribosomal protein S6 and 4E-BP1 are constitutively phosphorylated in CML cells. Experiments with specific inhibitors indicated the phosphorylation is downstream of Bcr-Abl kinase and the mammalian target of rapamycin (mTOR). These results suggest that Bcr-Abl may regulate translation of critical targets in CML cells via mTOR. They also provide a rationale for testing the combination of mTOR inhibitors with the Abl kinase inhibitor imatinib in patients with CML. The mTOR inhibitor rapamycin enhanced imatinib-mediated killing of CML cell lines in vitro, and it overcame imatinib resistance in cells with Bcr-Abl gene amplification.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Apoptosis / drug effects
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Benzamides
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Carrier Proteins / metabolism*
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Cell Cycle Proteins
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Drug Synergism
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Eukaryotic Initiation Factors
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Fusion Proteins, bcr-abl
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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Humans
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Imatinib Mesylate
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K562 Cells
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
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Mice
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / metabolism*
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Phosphorylation
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Piperazines / administration & dosage
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Piperazines / pharmacology
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Protein Kinase Inhibitors
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Protein Kinases / metabolism*
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / metabolism*
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Pyrimidines / administration & dosage
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Pyrimidines / pharmacology
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Ribosomal Protein S6 / metabolism*
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Sirolimus / administration & dosage
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
Substances
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Adaptor Proteins, Signal Transducing
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Benzamides
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Carrier Proteins
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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Eif4ebp1 protein, mouse
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Eukaryotic Initiation Factors
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Phosphoproteins
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Piperazines
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Protein Kinase Inhibitors
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Pyrimidines
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Ribosomal Protein S6
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Imatinib Mesylate
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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Protein-Tyrosine Kinases
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Fusion Proteins, bcr-abl
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TOR Serine-Threonine Kinases
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Sirolimus