ABL oncogenes and phosphoinositide 3-kinase: mechanism of activation and downstream effectors.
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.
Kharas
Michael G
MG
Center for Immunology and Department of Molecular Biology and Biochemistry, University of California at Irvine, Irvine, CA 92697-3900, USA.
Fruman
David A
DA
D000818:Animals; D004789:Enzyme Activation; D016313:Genes, abl / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human