This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Treatment of high risk acute lymphoblastic leukemia patients whom are positive for the Philadelphia chromosome mutation (ALL Ph+) which results in the fusion of BCR and Abl kinase (BCR/Abl), patients over the years have been extremely difficult. Recently, the standard hyperCVAD (Cyclophosphamide, Vincristine, Dexamethasone, and Doxorubicin) treatment for these patients was modified to include Gleevec (imatinib). The addition of Imatinib has been extremely successful and has increased the complete remission (CR) rate from 60 to 96% and the 2 year survival rate from about 40% of 85%. The mechanism by which Imatinib increases the efficacy of treatment is unclear. Cyclophosphamide metabolites, doxorubicin, and vincristine are all substrates of multidrug resistance protein 1 (MRP1/ABCC1). Recent studies have shown that increased expression and function of MRP1 is associated with a much poorer prognosis, a reduced CR, and a decreased 2 year survival (over 65% reduction) in ALL patients. Preliminary studies carried out in our lab suggest that BCR/Abl regulates MRP1 function via casein kinase 2 (CK2). CK2 is regulated by BCR/Abl and Src kinases. Interestingly, treatment of ALL Ph+ cells with CK2 inhibitors in combination with Imatinib has been shown to increase Gleevec efficacy (a decrease in the IC50 by 35%) (21). Therefore we hypothesize that inhibition of BCR-Abl with Imatinib down regulates CK2 activity and CK2-mediated induction of MRP1 function, this results in increased cellular accumulation of the CVAD chemotherapeutics (BCR-Abl?CK2?MRP1). In this proposal we will: 1) Determine the direct mechanism by which BCR/Abl induces MRP1 function, 2) Determine the role of CK2 in BCR/Abl-mediated induction of MRP1 function, and 3) Test our hypothesis in a Ph+ ALL tissue culture model system, Sup-B15 cells and directly in patient primary cells obtained from the University of Kentucky clinic in collaboration with Dr. Dianna Howard.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRR1-RI-B (01))
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University of Kentucky
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