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.
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 10mg/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.
Isotani
Mayu
M
Department of Veterinary Clinical Pathology, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino-shi, Tokyo 180-8602, Japan.
Tamura
Kyoichi
K
Yagihara
Hiroko
H
Hikosaka
Michiko
M
Ono
Kenichiro
K
Washizu
Tsukimi
T
Bonkobara
Makoto
M
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001483:Base Sequence; D001549:Benzamides; D002371:Cat Diseases / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D002415:Cats; D005091:Exons; D018095:Germ-Line Mutation; D000068877:Imatinib Mesylate; D008297:Male; D034721:Mastocytosis, Systemic / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000662:veterinary*; D008969:Molecular Sequence Data; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D012334:RNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000662:veterinary; D020080:Tandem Repeat Sequences
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012334:RNA, Neoplasm; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit