Activating Mutations ofc-Kitat Codon 816 Confer Drug Resistance in Human Leukemia Cells

Abstract

An improved understanding of how leukemia cells grow and become resistant to treatment remains critical for developing more effective therapies. We have identified activating mutations of c-kit at codon 816 (Asp⁸¹⁶) from a revertant of the cytokine-dependent acute myeloid leukemia (AML) cell line, MO7e (D816H), and de novo childhood AML (D816N). Following transduction of the mutant c-kit cDNAs, MO7e cells acquire a growth advantage and resistance to apoptosis in response to chemotherapeutic drugs and ionizing radiation, in addition to cytokine-independent survival. Although stimulation of mutant c-kit-bearing MO7e cells with stem cell factor (SCF), a ligand for c-Kit, does not have a significant effect on cell proliferation, SCF further inhibits apoptosis induced by cytotoxic agents. These results suggest a potentially important role of Asp⁸¹⁶ mutations of c-kit in both malignant cell proliferation and resistance to therapy.