Clinical implications of c-Kit mutations in acute myelogenous leukemia.
c-Kit is a receptor tyrosine kinase (RTK) with a pivotal role in melanogenesis, gametogenesis, and hematopoiesis. Aberrantly activated RTK and related downstream signaling partners were identified as key elements in the molecular pathogenesis of several malignancies. This finding culminated in a two-class model integrating constitutive activating and maturation arrest-inducing mutations as key elements for the pathogenesis of acute myelogenous leukemia (AML). c-Kit is expressed by myeloblasts in about 60% to 80% of patients, and the most frequently observed activating RTK mutations in AML (next to FLT3) are mutations or internal tandem duplications in c-Kit, with an overall incidence of 17%. The identification of small-molecule tyrosine kinase inhibitors capable of blocking key kinase switches introduced a paradigm change in the treatment of diseases like gastrointestinal stromal tumors and chronic myelogenous leukemia. Despite encouraging preclinical data, it appears that a complex clonal disease like AML will probably benefit from a synergistic approach of targeted drugs used (at least for now) in combination with conventional chemotherapy.
Malaise
Muriel
M
Department of Pediatrics, University of Ulm, Eythstrasse 24, 89075 Ulm, Germany.
Steinbach
Daniel
D
Corbacioglu
Selim
S
D000208:Acute Disease; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D016896:Treatment Outcome
D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit