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Identification of a c-kit exon 8 internal tandem duplication in a feline mast cell tumor case and its favorable response to the tyrosine kinase inhibitor imatinib mesylate

Author:
Isotani, M., Tamura, K., Yagihara, H., Hikosaka, M., Ono, K., Washizu, T., Bonkobara, M.
Source:
Veterinary immunology and immunopathology 2006 v.114 no.1-2 pp. 168-172
ISSN:
0165-2427
Subject:
sequence analysis, neoplasms, cats, proto-oncogenes, mutation, amino acid sequences, enzyme inhibitors, pets, mast cells, phosphotransferases (kinases), pathogenesis, protein phosphorylation, exons
Abstract:
The gain-of-function mutations within c-kit, a protooncogene encoding KIT, induce constitutive ligand-independent kinase activation and are important for the pathogenesis of mast cell proliferative disease in humans as well as in dogs. Despite the clinical importance of feline mast cell tumors, no mutation has been shown within the c-kit gene in cats. In the present report, we analyzed the c-kit nucleotide sequence in the case of a cat that showed systemic mastocytosis and mastocytemia. Within the c-kit cDNA prepared from the malignant mast cells, we identified an 12-bp internal tandem duplication at the region corresponding to exon 8, resulting in a four amino acid insertion between residues Thr418 and His419 within the fifth immunoglobulin-like domain of KIT. The cat underwent therapy with the kinase inhibitor imatinib mesylate (Gleevec) at a dose of 10 mg/kg. The tumor masses greatly responded and were undetectable after 5 weeks of treatment. Correspondingly, the number of mast cells in the peripheral blood was markedly reduced. It is, therefore, considered that the internal tandem duplication within the domain contributes to the neoplastic transformation of mast cells in the cat by increasing KIT phosphorylation.
Agid:
693983