Abstract
Bcr-Abl-expressing leukemic cells are highly resistant to apoptosis induced by chemotherapeutic drugs. Although a number of signaling molecules have been shown to be activated by the Bcr-Abl kinase, the antiapoptotic pathway triggered by this oncogene has not been elucidated. Here, we show that the interleukin 3-independent expression of the antiapoptotic protein, Bcl-xL, is induced by Bcr-Abl through activation of signal transducer and activator of transcription (Stat)5. Inhibition of the Bcr-Abl kinase activity in Bcr-Abl-expressing cell lines and CD34(+) cells from chronic myelogenous leukemia (CML) patients induces apoptosis by suppressing the capacity of Stat5 to interact with the bcl-x promoter. Interestingly, after inhibition of the Bcr-Abl kinase, the expression of Bcl-xL is downregulated more rapidly in chronic phase than in blast crisis CML cells, suggesting an involvement of this protein in disease progression. Overall, we describe a novel antiapoptotic pathway triggered by Bcr-Abl that may contribute to the resistance of CML cells to undergo apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis* / genetics
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Blast Crisis / enzymology
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Blast Crisis / metabolism
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Blast Crisis / pathology
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology
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Down-Regulation
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Fusion Proteins, bcr-abl / antagonists & inhibitors*
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Fusion Proteins, bcr-abl / genetics
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Fusion Proteins, bcr-abl / metabolism
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Fusion Proteins, bcr-abl / physiology
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Humans
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K562 Cells
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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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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Leukemia, Myeloid, Chronic-Phase / enzymology
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Leukemia, Myeloid, Chronic-Phase / metabolism
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Leukemia, Myeloid, Chronic-Phase / pathology
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Milk Proteins*
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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STAT5 Transcription Factor
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Signal Transduction* / genetics
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / genetics
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Trans-Activators / metabolism
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Trans-Activators / physiology
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Transfection
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Up-Regulation
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bcl-X Protein
Substances
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BCL2L1 protein, human
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DNA-Binding Proteins
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Milk Proteins
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Proto-Oncogene Proteins c-bcl-2
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STAT5 Transcription Factor
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Trans-Activators
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bcl-X Protein
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Protein-Tyrosine Kinases
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Fusion Proteins, bcr-abl