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Kohl, T.M. ; Schnittger, S. ; Ellwart, J.W. ; Hiddemann, W.* ; Spiekermann, K.

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 105, 3391 (2005)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 105, Issue: 8, Pages: 3391 Article Number: , Supplement: ,
Publisher American Society of Hematology
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Immunology (IMI)
CCG Pathogenesis of Acute Myeloid Leukemia (KKG-KPL)