Signal transducer and activator of transcription 3 activation is required for Asp816 mutant c-Kit-mediated cytokine-independent survival and proliferation in human leukemia cells

Activating mutations of c-kit at codon 816 (Asp(816)) have been implicated in a variety of malignancies, including acute myeloid leukemia (AML), The mutant c-Kit receptor confers cytokine-independent survival of leukemia cells and induces tumorigenicity. Changes in the signal transduction pathways responsible for Asp(816) mutant c-Kit-mediated biologic effects are largely undefined, The results of this study show that Asp(816) mutant c-Kit induces constitutive activation of signal transducer and activator of transcription 3 (STAT3) and STAT1, and up-regulates STAT3 downstream targets, Bcl-x(L) and c-myc, The phosphatidylinositol-3-kinase (PI-3K)/Akt pathway, but not the Ras-mediated mitogen-activated protein (MAP) kinase pathway, is also constitutively activated by Asp(816) mutant c-Kit, Suppression of STAT3 activation by a dominant negative molecule in MO7e leukemia cells transduced with mutant c-kit inhibits stem cell factor (SCF)-independent survival and proliferation, accompanied by the downregulation of Bcl-xL and c-myc, However, activated STAT3 does not appear to be the sole mediator that is responsible for the phenotypic changes induced by Asp(816) mutant c-Kit, because expression of constitutively activated STAT3 in MO7e cells does not completely reconstitute cytokine independence, Activation of other signaling components by mutant c-Kit, such as those in the PI-3K/Akt pathway, is demonstrated and may also be needed for the mutant c-Kit-mediated biologic effects, The investigation of altered signal transduction pathways and the resulting functional consequences mediated by Asp(816) mutant c-Kit should provide important information for the characterization of subsets of leukemia and potential molecular pathways for therapeutic targeting. (Blood, 2001;97:3558-3567) (C) 2001 by The American Society of Hematology.