Signal transducer and activator of transcription 3 activation is required for Asp(816) 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 down-regulation of Bcl-x(L) 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;97:3559-3567)
Ning
Z Q
ZQ
Division of Hematology/Oncology, Children's Hospital Medical Center, Cincinnati, OH, USA.
Li
J
J
Arceci
R J
RJ
D001224:Aspartic Acid / Q000235:genetics; D002455:Cell Division; D002470:Cell Survival; D003062:Codon; D016207:Cytokines / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000502:physiology*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D001224:Aspartic Acid; D003062:Codon; D016207:Cytokines; D004247:DNA; D004268:DNA-Binding Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019009:Proto-Oncogene Proteins c-kit; D050796:STAT3 Transcription Factor; D019089:Stem Cell Factor; D015534:Trans-Activators; C494086:STAT3 protein, human; C494918:AKT1 protein, human