STAT3 activation is required for Asp(816) mutant c-Kit induced tumorigenicity

Activating mutations of c-kit at codon 816 (Asp(816)) have been identified in variety of malignancies, including acute myeloid leukemia (AML), mastocy tosis and germ cell tumors. The mutant c-Kit receptor confers cytokine inde pendence and induces tumorigenicity. However, the molecular mechanisms, par ticularly the changes in the signal transduction pathways, responsible for these biological effects induced by mutant c-Kit are largely undefined. Usi ng the human embryonic kidney cell line, 293, we show in the current report that constitutive activation of STAT3 and STAT1 is associated with D816H m utant c-Kit. Transfection of dominant negative STAT3, but not STAT1 inhibit s mutant c-Kit mediated anchorage-independent growth in vitro and tumor for mation in vivo. Expression of constitutively activated STAT3 restores the m utant c-Kit receptor's transforming ability in 293 cells. These results dem onstrate that activation of STAT3 by Asp(816) mutant c-Kit is required for the anchorage-independent growth and tumorigenicity induced by Asp(816) mut ant c-Kit.