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Blood, 1 June 2001, Vol. 97, No. 11, pp. 3559-3567
NEOPLASIA
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, and
Robert J. Arceci
From the Division of Hematology/Oncology, Children's
Hospital Medical Center, Cincinnati, OH; and the Division of Pediatric
Oncology, Johns Hopkins Oncology Center, Baltimore, MD.
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.
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