Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5 …
The Journal of experimental medicine, 2000•rupress.org
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 …
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 …
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.
rupress.org