Mutations in the fifth immunoglobulin-like domain of kit are common and potentially sensitive to imatinib mesylate in feline mast cell tumours
Mutations in the fifth immunoglobulin-like domain of kit are common and potentially sensitive to imatinib mesylate in feline mast cell tumours
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DOI：
10.1111/j.1365-2141.2009.07926.x
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发表时间：
2010-01-01
影响因子：
6.5
通讯作者：
Bonkobara, Makoto
中科院分区：
文献类型：
--
作者：
Isotani, Mayu;Yamada, Osamu;Bonkobara, Makoto
P>本研究的目的是调查猫肥大细胞瘤（MCT）中 KIT 的突变状态，并在体外和猫的临床病例中检查酪氨酸激酶抑制对突变 Kit 磷酸化的影响。 KIT 的序列分析识别出 42/62 个 MCT 中的突变（67 个中心点，7%）。绝大多数突变分布在外显子8和9，这两个外显子都编码kit的第五个免疫球蛋白样结构域（IgD）。然后，第五种 IgD 发生突变的所有五种类型的试剂盒均在 293 细胞中表达，并检查磷酸化状态。突变试剂盒蛋白表现出配体依赖性磷酸化。酪氨酸激酶抑制剂甲磺酸伊马替尼抑制转染细胞中这些突变试剂盒蛋白的磷酸化。在一项对 10 只患有 MCT 的猫进行的临床研究中，在 7/8 只肿瘤细胞中第五个 IgD 突变的猫中观察到对甲磺酸伊马替尼的有益反应。因此，猫 MCT 中试剂盒第五个 IgD 的突变似乎很常见，并且对甲磺酸伊马替尼可能敏感。这些数据提供了儿童肥大细胞增多症的体内模型，其中试剂盒的第五个 IgD 也发生突变。
P>The purpose of the current study was to investigate the mutation status of KIT in feline mast cell tumours (MCTs) and to examine the effects of tyrosine kinase inhibition on the phosphorylation of mutant kit in vitro and in clinical cases of cats. Sequence analysis of KIT identified mutations in 42/62 MCTs (67 center dot 7%). The vast majority of the mutations were distributed in exons 8 and 9, both of which encode the fifth immunoglobulin-like domain (IgD) of kit. All five types of kit with a mutation in the fifth IgD were then expressed in 293 cells and examined for phosphorylation status. The mutant kit proteins showed ligand-independent phosphorylation. The tyrosine kinase inhibitor imatinib mesylate suppressed the phosphorylation of these mutant kit proteins in transfectant cells. In a clinical study of 10 cats with MCTs, beneficial response to imatinib mesylate was observed in 7/8 cats that had a mutation in the fifth IgD of kit in tumour cells. Mutations in the fifth IgD of kit thus appear to be common and potentially sensitive to imatinib mesylate in feline MCTs. These data provide an in vivo model for paediatric mastocytosis where mutations in the fifth IgD of kit also occur.