Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate.
Multiple genetic alterations are required to induce acute myelogenous leukemia (AML). Mutations in the extracellular domain of the KIT receptor are almost exclusively found in patients with AML carrying translocations or inversions affecting members of the core binding factor (CBF) gene family and correlate with a high risk of relapse. We demonstrate that these complex insertion and deletion mutations lead to constitutive activation of the KIT receptor, which induces factor-independent growth of interleukin-3 (IL-3)-dependent cells. Mutation of the evolutionary conserved amino acid D419 within the extracellular domain was sufficient to constitutively activate the KIT receptor, although high expression levels were required. Dose-dependent growth inhibition and apoptosis were observed using either the protein tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec) or by blocking the phosphoinositide-3-kinase (PI3K)-AKT pathway. Our data show that the addition of kinase inhibitors to conventional chemotherapy might be a new therapeutic option for CBF-AML expressing mutant KIT.
Cammenga
Jörg
J
Molecular Pathology Group, Heinrich-Pette-Institut, PO Box 201 652, D-20206 Hamburg, Germany.
Horn
Stefan
S
Bergholz
Ulla
U
Sommer
Gunhild
G
Besmer
Peter
P
Fiedler
Walter
W
Stocking
Carol
C
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001549:Benzamides; D050660:Core Binding Factors / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D019089:Stem Cell Factor / Q000235:genetics*
D000970:Antineoplastic Agents; D001549:Benzamides; D050660:Core Binding Factors; D010879:Piperazines; D011743:Pyrimidines; D019089:Stem Cell Factor; D000068877:Imatinib Mesylate