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

Zhi Qiang Ning, Jin Li, Robert J. Arceci

Research output: Contribution to journalArticlepeer-review

Abstract

Activating mutations of c-kit at codon 816 (Asp816) 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 Asp816 mutant c-Kit-mediated biologic effects are largely undefined. The results of this study show that Asp816 mutant c-Kit induces constitutive activation of signal transducer and activator of transcription 3 (STAT3) and STAT1, and up-regulates STAT3 downstream targets, Bcl-XL 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 ASP816 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 down-regulation 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 Asp816 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 ASP816 mutant c-Kit should provide important information for the characterization of subsets of leukemia and potential molecular pathways for therapeutic targeting.

Original languageEnglish (US)
Pages (from-to)3559-3567
Number of pages9
JournalBlood
Volume97
Issue number11
DOIs
StatePublished - Jun 1 2001

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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