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)

Bcr-Abl-expressing leukemic cells are highly resistant to apoptosis induced by chemotherapeutic drugs. Although a number of signaling molecules have b een 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-x(L) , is induced by Bcr-Abl through activation of signal transducer and activat or of transcription (Stat)5. Inhibition of the Bcr-Abl kinase activity in B cr-Abl-expressing cell lines and CD34(+) cells from chronic myelogenous leu kemia (CML) patients induces apoptosis by suppressing the capacity of Stat5 to interact with the bcl-x promoter. Interestingly, after inhibition of th e Bcr-Abl kinase, the expression of Bcl-x(L) 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 antiap optotic pathway triggered by Bcr-Abl that may contribute to the resistance of CML cells to undergo apoptosis.