RESUMO
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.
Assuntos
Mastocitose/genética , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Doença Aguda , Adulto , Antineoplásicos/química , Antineoplásicos/farmacologia , Sítios de Ligação , Criança , Desenho de Fármacos , Ativação Enzimática/genética , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Neoplasias Gastrointestinais/genética , Neoplasias Hematológicas/genética , Humanos , Leucemia Mieloide/genética , Ligantes , Linfoma não Hodgkin/genética , Mastocitose/classificação , Mastocitose/tratamento farmacológico , Mesenquimoma/genética , Transtornos Mieloproliferativos/genética , Neoplasias Nasais/genética , Neoplasias dos Seios Paranasais/genética , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-kit/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/metabolismo , Fator de Células-Tronco/antagonistas & inibidores , Fator de Células-Tronco/fisiologiaRESUMO
c-kit protooncogene encodes a type III transmembrane receptor kinase, the stem cell factor receptor, or KIT. The ligand of the KIT. stem cell factor, is a cytokine that stimulates mast cell growth and differentiation. We have studied immunohistochemically KIT expression in 23 canine mast cell tumors (MCTs), 10 histiocytomas, 5 malignant melanomas, and in 2 cell lines derived from mast cells (HMC-1, human and C2, canine). As expected, KIT was detected both in the human mast cell leukemia cell line (HMC- ) and in the canine mastocytoma cell line C2. In normal canine skin, KIT expression was confined to mast cells. All canine MCTs expressed KIT, although the intensity of the staining reaction varied considerably among the 23 neoplasms. Grade III tumors showed the highest expression of KIT, whereas grade I tumors showed the lowest expression of KIT. Two patterns of KIT expression were detected in mast cells. In normal canine mast cells and in some neoplastic mast cells, KIT appeared mainly on the cell membrane. However, in many canine MCTs, KIT is accumulated in the cytoplasm, usually near the cell nucleus. The meaning of these two patterns is not clear. Expression of KIT could not be detected immunohistochemically in any of the other neoplasias investigated. According to our results, it can be concluded that most, if not all, canine MCT express KIT. Furthermore, there is an inverse correlation between the degree of differentiation and the expression of KIT. Moreover, according to our results, KIT can be used as a reliable immunohistochemical marker for canine mast cells and undifferentiated mast cell tumors.
