Blockade of the bcr-abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by supressing STAT5-dependent expression of bcl-xl

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 anti-apopotic pathway triggered by this oncogene has not been elucidated. Here, we show in cell lines (K562, MO7E-p210) and primary CD34+ cells from patients with CML, that the IL-3-independent expression of the anti-apoptotic protein Bcl-x L is induced by Bcr-Abl through activation of signal transducer and activator of transcription (Stat)5. Inhibition of the Bcr-Abl kinase activity by STI571 (specific inhibitor of Abl tyrosine kinase activity) induces apoptosis of CML cells by supressing the capacity of Stat5 to interact with the bcl-x promoter as demonstrated by EMSA. STI571 mediated apoptosis and downregulation of bcl-x was prevented by incubation with IL3. Transduction of K562 with a STAT5 dominant negative resulted in apoptosis of K562. Interestingly, cells from patients with CML in advanced phase were more resistant to STI571 induced apoptosis than patients in chronic phase. Overall, we describe a novel anti-apoptotic pathway triggered by Bcr-Abl that involves STAT5 mediated upregulation of bcl-x. This pathway may be successfully inhibited by the Abl kinase inhibitor STI571.