title: Activating mutations of c-kit at 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 (Asp(816) ) 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 Asp(816) mutations of c-kit in both malignant cell proliferation and resistance to therapy.
authors.affiliation: Division of Hematology/Oncology, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Ning
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: R J
authors.initials: RJ
authors.lastname: Arceci
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002648:Child; D003062:Codon / Q000235:genetics; D016207:Cytokines / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D015479:Leukemia, Myelomonocytic, Acute / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000494:pharmacology*; D019089:Stem Cell Factor / Q000187:drug effects; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects
chemical_list: D000970:Antineoplastic Agents; D003062:Codon; D016207:Cytokines; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit