Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy.
Mutations causing constitutive activation of KIT have been shown to be causative in some forms of mastocytosis, and several types of mutations have been associated with myeloproliferative disorders (MPDs), acute myelogenous leukemia (AML), sinonasal lymphomas, and gastrointestinal stromal tumors (GIST). We divide these activating mutation into two types - 'regulatory type' mutations, which affect regulation of the kinase molecule, and 'enzymatic pocket type' mutations, which alter the amino acid sequence directly forming the enzymatic site. KIT inhibitors have been suggested as therapeutic drugs for these conditions, but different types of activating mutations respond differentially to KIT inhibitors, so classification of individuals on the basis of specific mutations is necessary to guide therapy.
Longley
B J
BJ
Department of Dermatology and Pathology, Columbia University, 630 West 168th Street, VC-15-202, New York, NY 10031, USA.
Reguera
M J
MJ
Ma
Y
Y
D000208:Acute Disease; D000328:Adult; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002648:Child; D015195:Drug Design; D004789:Enzyme Activation / Q000235:genetics; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005770:Gastrointestinal Neoplasms / Q000235:genetics; D019337:Hematologic Neoplasms / Q000235:genetics; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics; D008024:Ligands; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics; D008415:Mastocytosis / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D008637:Mesenchymoma / Q000235:genetics; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics; D009669:Nose Neoplasms / Q000235:genetics; D010255:Paranasal Sinus Neoplasms / Q000235:genetics; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D019089:Stem Cell Factor / Q000037:antagonists & inhibitors / Q000502:physiology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit