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The BCR-ABL kinase plays an essential role in the pathogenesis of chronic myeloid leukemia (CML). The roles of many of the effectors of BCR-ABL are characterized in some detail, and mostly by in vitro studies, but little is known of their pathways that promote transformed hematopoietic cells to evade apoptosis in vivo. Here, we report a novel mechanism by which BCR-ABL can promote survival and prevent apoptosis of leukemic hematopoietic cells in a murine model of BCR-ABL-induced CML. Our studies demonstrate that BCR-ABL expression in hematopoietic cells leads to down-regulation of the protein level and transcriptional activity of members of Forkhead Transcription Factor family, i.e., FOXO3a, a key regulator of cellular survival. We have observed that the down-regulation of FOXO3a involves Akt-dependent phosphorylation and relocalization of FOXO3a in the cytoplasm. Additionally, we have observed that BCR-ABL expression also down-regulates the levels of FOXO3a protein through a proteasome-mediated pathway. Suppression of both FOXO3a activity and expression then lead to down-regulation of expression of FOXO3a transcriptional target molecules, such as TRAIL and Bim, causing evasion of transformed hematopoietic cells from apoptosis. Here we show that inhibition of the proteasome-mediated degradation pathway, using a proteasome inhibitor, bortezomib, causes regression of CML-like disease by preventing BCR-ABL-induced suppression of FOXO3a and the pro-apoptotic factors TRAIL and BIM. Our data delineate the involvement of FOXO3a, TRAIL and Bim in BCR-ABL-induced evasion of apoptosis and demonstrate the efficacy of bortezomib in the treatment of BCR-ABL-induced CML-like disease in vivo.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA