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 mu...

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Bibliographic Details
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
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Summary: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)
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2004-06-2068