Evasion from apoptosis is one of the less investigated hallmarks of cancer progression. The Bcr-Abl oncogene facilitates cytokine-independent growth of hematopoietic cells, which results in their enhanced proliferation and evasion from apoptosis. This process ultimately leads to chronic myeloid leukemia (CML). We recently reported that one mechanism by which Bcr-Abl expression promotes evasion from apoptosis in vitro is through the inhibition of FOXO3a-dependent transcription of several pro-apoptotic factors including TRAIL, as well as Bim and Hrk. The overall objective of this proposal is to elucidate the physiological role of FOXO3a and its downstream targets, TRAIL, Bim and Hrk, in Bcr-Abl-induced evasion from apoptosis and their involvement in Bcr-Abl-induced myeloproliferative disorders (MPD) in vivo. As is detailed in this proposal, we hypothesize that FOXO3a-dependent, Bcr-Abl-induced regulation of TRAIL, Bim and Hrk is a novel mechanism for regulating the tumorigenic activity of Bcr-Abl in vivo. Additionally, we posit that coordinate regulation of TRAIL, Bim and Hrk promotes Bcr-Abl-induced leukemia. Finally, we propose that Bcr-Abl supports evasion from apoptosis by instigating the proteasomal degradation of FOXO3a. Therefore, we hypothesize that targeting FOXO3a may be a therapeutic strategy to induce tumor-selective apoptosis in Bcr-Abl transformed cells.
The Specific Aims of this proposal are: 1) to determine the biological significance of FOXO3a transcription factor activity and consequent regulation of TRAIL expression in promoting Bcr-Abl-induced transformation of hematopoietic cells, 2) to determine whether Bcr-Abl also regulates Bim and Hrk expression in a FOXO3a dependent manner as a mechanism for apoptotic evasion in leukemic hematopoietic cells, 3) to determine the role of the proteasomal pathway in Bcr-Abl-mediated down-regulation of FOXO3a transcription factor. We will utilize diverse approaches to carry out these studies including molecular biology, cell biology, murine models for tumorigenicity and murine model for Bcr-Abl-induced leukemia. Taken together, these studies will lead to a better understanding of the mechanisms involved in leukemogenesis in general and to the characterization of novel molecular targets for treatment of CML. Finding a novel target is especially critical given that resistance to the currently used STI-571 therapy is emerging as a common problem. ? ?
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