Dysregulated protein-tyrosine kinases (TKs) are the cause of most cases of chronic myeloproliferative- ike diseases, and have also been implicated in the pathogenesis of some types of acute lymphoid leukemia/ ymphoblastic lymphoma of both B cell and T cell origin. Examples include the BCR-ABL fusion TK, product of the Ph chromosome translocation in chronic myeloid leukemia (CML), and the recently discovered JAK2 V617F mutant, found in most patients with polycythemia vera (PV). Current therapy for these diseases is nadequate. The TK enzymes are good targets for drug development in these malignancies, as illustrated by the success of imatinib mesylate, a small molecule inhibitor of BCR-ABL in CML. However, kinase inhibitor therapy of CML is limited by acquired and primary resistance of the disease to the inhibitor. In addition, there is an increasing appreciation that kinase inhibitors are unlikely to be curative when used alone, because the so-called leukemia """"""""stem cells"""""""" that initiate and maintain the disease are relatively insensitive to these drugs. A better understanding of the molecular pathogenesis of CML, PV, Ph+ B-cell acute lymphoblastic leukemia (B-ALL), and other hematologic malignancies associated with dysregulated TKs is needed to develop additional targeted therapies, and to build strategies to overcome or prevent resistance to kinase inhibitors and eradicate the disease. Accurate and quantitative mouse models of these diseases are essential tools in this effort, because they can address fundamental questions about mechanisms of leukemogenesis that are difficult or impossible to approach through studies of primary human leukemia cells or cell lines. The overall goal of this competing renewal application is to utilize established mouse models of Ph+ leukemia, including BCR-ABL-induced CML and B-ALL, and a new model of PV, to advance our understanding of the molecular pathophysiology of these diseases. To accomplish this goal, we will carry out two interdependent and integrated specific aims. In the first aim, we will analyze the molecular pathogenesis of these diseases and identify the signaling pathways that are critical for leukemogenesis in vivo. This will be accomplished through a multifaceted approach using TK mutants, mouse strains with targeted mutations in signaling molecules, and small molecule inhibitors targeting specific pathways. In the second aim, the leukemia-initiating or leukemia stem cells in these distinct diseases will be phenotypically and functionally characterized. These studies should generate important new knowledge about the pathogenesis of these diseases that will impact directly on improvements in therapy.
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