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.
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.
Kohl
Tobias M
TM
Department of Medicine III, University Hospital Grosshadern, CCG Leukemia, GSF-National Research Center for Environment and Health, Marchioninistrasse 25, 81377 Munich, Germany.
Schnittger
Susanne
S
Ellwart
Joachim W
JW
Hiddemann
Wolfgang
W
Spiekermann
Karsten
K
D000208:Acute Disease; D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D050660:Core Binding Factors; D005091:Exons; D017353:Gene Deletion; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008024:Ligands; D016296:Mutagenesis; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D050660:Core Binding Factors; D008024:Ligands; D009363:Neoplasm Proteins; D019089:Stem Cell Factor; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit