The BCR-Abl oncoprotein is directly linked to the pathogenesis of chronic myeloid leukemia and a subset of acute lymphocytic leukemias. BCR-Abl promotes tumorigenesis by increasing cellular proliferation and inhibiting cell death (apoptosis). However, the mechanism by which BCR-Abl prevents apoptosis remains largely unknown. In response to DNA damage, apoptotic signaling pathways converge on the mitochondria to release cytochrome c into the cytosol where it binds to a proapoptotic regulator, Apaf1. The cytochrome c/Apaf1 complex recruits and activates the cysteine protease caspase 9 to form an active proteolytic complex known as the apoptosome. Although BCR-Abl has been shown to exert its anti-apoptotic effects by preventing cytochrome c release, addition of purified BCR-Abl to an in vitro apoptosis system inhibited caspase activity after mitochondrial release of cytochrome c. Furthermore, caspase activity was inhibited when cytochrome c was added to lysates from BCR-Abl-expressing mammalian cells. Therefore, it is hypothesized that BCR-Abl directly modulates the apoptosome to inhibit apoptosis. The goal of this proposal is to elucidate the mechanism by which BCR-Abl inhibits the apoptosome to block cell death. The results from this study will reveal new apoptotic regulators that can eventually be targeted to sensitize resistant cells to chemotherapeutics.
