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

• Published in: Blood 2005-04, Vol.105 (8), p.3319-3321
• Main Authors: Kohl, Tobias M., Schnittger, Susanne, Ellwart, Joachim W., Hiddemann, Wolfgang, Spiekermann, Karsten
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Biological and medical sciences; Cell Division; Cell Line, Tumor; Core Binding Factors; Exons; Gene Deletion; Hematologic and hematopoietic diseases; Humans; Leukemia, Myeloid - genetics; Leukemia, Myeloid - metabolism; Leukemia, Myeloid - physiopathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Ligands; Medical sciences; 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
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-06-2068

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. (Blood. 2005;105:3319-3321)