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A mouse model of activating Met mutations.

机译:激活Met突变的小鼠模型。

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Tyrosine kinase-activating mutations in Met have been observed in hereditary papillary renal carcinomas (HPRC) and their transforming potential has been examined both in vitro and in tumor xenografts. To study the influence of these mutations in the mouse germline, we generated mice with targeted mutations in the murine met locus. Five mouse lines with mutant Met were created: WT, D1226N, Y1228C, M1248T, and M1248T/L1193V. Unexpectedly, the different mutant Met lines developed unique tumor profiles including carcinomas, sarcomas, and lymphomas. More surprising was that we observed non-random duplication of the mutant met allele in a majority of tumors from the mutant mouse lines. This selective chromosomal amplification has been observed in patients with HPRC. This study illustrates the importance of activating Met mutations in tumorigenesis and indicates that mutations within the kinase domain distinctly affect downstream signaling. Our Met mutant mice will provide a valuable model for testing Met inhibitors on tumors containing activating mutations present in human cancers and for understanding the molecular events critical for Met-mediated tumorigenesis.
机译:在遗传性乳头状肾癌(HPRC)中已经观察到Met中的酪氨酸激酶激活突变,并且已经在体外和肿瘤异种移植物中检查了它们的转化潜力。为了研究这些突变对小鼠种系的影响,我们在鼠类基因座中产生了具有目标突变的小鼠。创建了五个具有突变Met的小鼠品系:WT,D1226N,Y1228C,M1248T和M1248T / L1193V。出乎意料的是,不同的突变Met系发展出独特的肿瘤特征,包括癌,肉瘤和淋巴瘤。更令人惊讶的是,我们在来自突变小鼠系的大多数肿瘤中观察到了突变的met等位基因的非随机复制。在HPRC患者中已经观察到这种选择性的染色体扩增。这项研究说明了激活Met突变在肿瘤发生中的重要性,并表明激酶域内的突变明显影响下游信号传导。我们的Met突变小鼠将提供一种有价值的模型,用于测试包含人类癌症中存在的激活突变的肿瘤上的Met抑制剂,并了解对于Met介导的肿瘤发生至关重要的分子事件。

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