Activating Met mutations produce unique tumor profiles in mice with selective duplication of the mutant allele

Carrie Graveel, Yanli Su, Julie Koeman, Ling Mei Wang, Lino Tessarollo, Michele Fiscella, Carmen Birchmeier, Pamela Swiatek, Roderick Bronson, George Vande Woude

Research output: Contribution to journalArticlepeer-review

94 Scopus citations

Abstract

Tyrosine kinase-activating mutations in Met have been observed in hereditary papillary renal carcinomas as well as in other cancers. These mutations have been examined in several in vitro systems, where they cause constitutive Met activation, focus formation, and cell motility, and are tumorigenic in xenografts. To study the influence of these mutations on tumorigenesis in vivo, we generated mice with targeted mutations in the murine met locus. The following five mouse lines with mutant Met were created: WT, D1226N, Y1228C, M1248T, and M1248T/L1193V. We observed that mice harboring D1226N, Y1228C, and M1248T/L1193V mutations developed a high frequency of sarcomas and some lymphomas, whereas the M1248T mice developed carcinomas and lymphomas. Of considerable interest, we observed trisomy of chromosome 6 and duplication of the mutant met allele in a majority of the tumors, similar to what has been reported in patients with hereditary renal papillary carcinomas. These results demonstrate that activating Met mutations and met amplification play key roles in promoting tumorigenesis in vivo. Moreover, our findings show that different mutations in the Met kinase domain can influence the types of cancers that develop.

Original languageEnglish
Pages (from-to)17198-17203
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number49
DOIs
StatePublished - 7 Dec 2004
Externally publishedYes

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