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ABL Oncogenes and Phosphoinositide 3-Kinase: Mechanism of Activation and Downstream Effectors

Center for Immunology and Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, California

Requests for reprints: David A. Fruman, Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, CA 92697-3900. Phone: 949-824-1947; Fax: 949-824-8551; E-mail: dfruman{at}uci.edu.

The BCR-ABL oncogene is responsible for most cases of chronic myelogenous leukemia and some acute lymphoblastic leukemias. The fusion protein encoded by BCR-ABL possesses an aberrantly regulated tyrosine kinase activity. Imatinib mesylate (Gleevec, STI-571) is an inhibitor of ABL tyrosine kinase activity that has been remarkably effective in slowing disease progression in patients with chronic phase chronic myelogenous leukemia, but the emergence of imatinib resistance underscores the need for additional therapies. Targeting signaling pathways activated by BCR-ABL is a promising approach for drug development. The study of signaling components downstream of BCR-ABL and the related murine oncogene v-Abl has revealed a complex web of signals that promote cell division and survival. Of these, activation of phosphoinositide 3-kinase (PI3K) has emerged as one of the essential signaling mechanisms in ABL leukemogenesis. This review describes molecular mechanisms by which PI3K is activated and the downstream PI3K effectors that propagate the signal to promote myeloid and lymphoid transformation. Of particular recent interest is the mammalian target of rapamycin, a PI3K-regulated kinase that regulates protein synthesis and contributes to leukemogenesis.

Key Words: Leukemia Lymphoma • ABL • Phosphatidylinositol 3-Kinase • AKT • mTOR

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