Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-xL.
J Exp Med
; 191(6): 977-84, 2000 Mar 20.
Article
in En
| MEDLINE
| ID: mdl-10727459
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.
Full text:
1
Database:
MEDLINE
Main subject:
Protein-Tyrosine Kinases
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
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Signal Transduction
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Trans-Activators
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Fusion Proteins, bcr-abl
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Apoptosis
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Proto-Oncogene Proteins c-bcl-2
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DNA-Binding Proteins
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Milk Proteins
Limits:
Humans
Language:
En
Journal:
J Exp Med
Year:
2000
Type:
Article
Affiliation country:
Spain