Activating mutations of c-kit at codon 816 confer drug resistance in human leukemia cells

Leuk Lymphoma. 2001 May;41(5-6):513-22. doi: 10.3109/10428190109060342.


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.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / radiation effects
  • Cell Division / drug effects
  • Cell Division / genetics
  • Child
  • Codon / genetics
  • Cytokines / pharmacology
  • Drug Resistance, Neoplasm / genetics
  • Humans
  • Leukemia / drug therapy*
  • Leukemia / genetics
  • Leukemia / pathology*
  • Leukemia, Myelomonocytic, Acute / etiology
  • Leukemia, Myelomonocytic, Acute / genetics
  • Leukemia, Myelomonocytic, Acute / pathology*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutation*
  • Neoplasm Transplantation
  • Proto-Oncogene Proteins c-kit / genetics*
  • Proto-Oncogene Proteins c-kit / pharmacology*
  • Stem Cell Factor / drug effects
  • Transduction, Genetic
  • Transplantation, Heterologous
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / radiation effects


  • Antineoplastic Agents
  • Codon
  • Cytokines
  • Stem Cell Factor
  • Proto-Oncogene Proteins c-kit