REGULATION OF BCL2 BY APOPTOTIC PATHWAYS IN LEUKEMIA

St. Jude Children'S Research Hospital, Memphis TN

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Abstract

The majority of leukemia harbor lesions which directly or indirectly activate the expression or activity of the c-Myc or E2F oncogenes which function as master regulators of the cell cycle. However, enforced expression of c-Myc or E2F-1 in hematopoietic progenitors also activates the apoptotic program and rapidly induce cell death when cells are deprived of survival factors. We have demonstrated that expression of Bcl-2, an oncogene which specifically functions to suppress apoptosis, is tightly regulated by pathways which suppress or activate apoptosis. Overexpression of oncogenes which trigger apoptosis leads to suppression of Bcl-2 protein and RNA expression and the experiments in Aim number 1 will determine the mechanism of Bcl-2 suppression. Modulating Bcl-2 levels in cells overexpressing c-Myc orE2F-1 demonstrated that specific thresholds of Bcl-2 are critical in regarding cell survival. Therefore, the experiments of Aim number 2 will determine, in agenetic fashion, the requirement for Bcl-2, and for its dimerization partner Bax, in c- Myc mediated transformation and apoptosis. Finally, we have demonstrated that Bcl-2 is also targeted by pathways which suppress apoptosis. Specifically, overexpression of another Bcl-2 family member, Bcl-XL, which is also a cell death antagonist and is selectively activated (by retroviral inssertions) in cytokine-independent murine leukemia also suppresses Bcl-2 expression. By contrast, overexpression of Bcl-2 does not influence levels of Bcl-XL or other family members. Therefore, this suggests that there is hierarchical regulation on Bcl-2 family members. Experiments of Aim number 3 will address the mechanism by which Bcl-2 is suppressed by Bcl-XL and determine the hierarchical relationships of Bcl-2 family members. Thus, our studies suggest that although Bcl-2 and Bcl-XL are structurally related, they are differentially regulated and are selectively targeted by unique pathways during myelopoiesis and leukemogenesis. In particular, our results suggest the hypothesis that levels of Bcl-2 are dynamically regulated by pathways that activate or suppress apoptosis and that this may play a critical role in the deletion of cells in hematopoiesis and leukemia.