Investigating the SRC kinase HCK functions in Chronic Myelogenous Leukemia using chemical genetics methods.

摘要: The hallmark of chronic myelogenous leukemia (CML) is a chromosomal translocation between the c-abl gene (chromosome 9) and bcr 22). This event gives rise to BcrAbl, chimeric protein with constitutive tyrosine kinase activity that drives pathogenesis disease. Imatinib, Bcr-Abl inhibitor frontline therapy in CML. Although imatinib very effective phase CML, patients advanced stages develop resistance. An increased understanding signaling pathways implicated CML resistance critical development improved therapies. Previous work our laboratory found A-419259, broad-spectrum Src family (SFK) induces growth arrest apoptosis cells, suggesting SFKs are required for transformation myeloid progenitors. Additionally, Hck couples BcrAbl Stat5 activation which may contribute survival. Furthermore, studies on samples from some imatinib-resistant expression Lyn. In this dissertation, using two chemical genetic methods, I addressed contribution To explore individual signaling, developed an A419259-resistant mutant (Hck-T338M). Expression Hck-T338M fully protected K562 cells A-419259-induced apoptosis, effect correlated sustained activation. addition, partially against inhibition induced by A-419259. These suggest plays non-redundant role as key downstream survival partner Bcr-Abl.I also tested whether overexpression was sufficient induce cells. For study, (Hck-T338A) uniquely sensitive NaPP1, analog generic SFK pyrrazolo-pyrimidine 1. Overexpression or Hck-T338A imatinib-dependent arrest. NaPP1 reversed K562-Hck-T338A Hck-induced requires activity. Taken together, my validates target apoptosis-inducing drugs likely be patients.