KIT exon 8 mutations associated with core-binding factor (CBF)-acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor

Blood. 2005 Apr 15;105(8):3319-21. doi: 10.1182/blood-2004-06-2068. Epub 2004 Dec 23.


KIT exon 8 mutations are located in the extracellular portion of the receptor and are strongly associated with core-binding factor (CBF)-acute myeloid leukemia (AML). To characterize the functional role of these mutants, we analyzed the proproliferative and antiapoptotic potential of 3 KIT exon 8 mutations in interleukin 3 (IL-3)-dependent Ba/F3 cells. All KIT exon 8 mutants induced receptor hyperactivation in response to stem cell factor (SCF) stimulation in terms of proliferation and resistance toward apoptotic cell death. A representative KIT exon 8 mutant showed spontaneous receptor dimerization, phosphorylation of mitogen-activated protein kinase (MAPK), and conferred IL-3-independent growth to Ba/F3 cells. MAPK and phosphatidylinositol 3-kinase (PI3-kinase) activation was essential for the phenotype of this mutant. Additionally, imatinib inhibited proliferation of KIT exon 8 mutant-expressing Ba/F3 cells. Our data show that KIT exon 8 mutations represent gain-of-function mutations and might represent a new molecular target for treatment of CBF leukemias.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Cell Division
  • Cell Line, Tumor
  • Core Binding Factors
  • Exons
  • Gene Deletion
  • Humans
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / metabolism
  • Leukemia, Myeloid / physiopathology
  • Ligands
  • Mutagenesis
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-kit / genetics*
  • Proto-Oncogene Proteins c-kit / metabolism*
  • Signal Transduction
  • Stem Cell Factor / metabolism
  • Stem Cell Factor / pharmacology*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • Core Binding Factors
  • Ligands
  • Neoplasm Proteins
  • Stem Cell Factor
  • Transcription Factors
  • Proto-Oncogene Proteins c-kit