Journal article
A knock-in mouse model of gastrointestinal stromal tumor harboring Kit K641E
Cancer research (Chicago, Ill.), Vol.65(15), pp.6631-6639
2005
DOI: 10.1158/0008-5472.CAN-05-0891
PMID: 16061643
Abstract
A mouse model of gastrointestinal stromal tumor (GIST) has been developed by a knock-in gene targeting strategy, which introduced a Kit gene K641E mutation, originally identified in sporadic human GISTs and in the germ line of familial GIST syndrome patients. Homozygous and heterozygous Kit K641E mice develop gastrointestinal pathology with complete penetrance and all Kit K641E homozygotes die by age 30 weeks due to gastrointestinal obstruction by hyperplastic interstitial cells of Cajal (ICC) or GISTs. Heterozygous mice have less extensive ICC hyperplasia and smaller GISTs, suggesting a dose-response relationship between oncogenically activated Kit and ICC proliferation. Immunoprecipitation and Western blotting reveal GISTs to contain abundant phosphorylated/activated Kit. In addition to ICC hyperplasia and GISTs, homozygous Kit K641E mice exhibit loss-of-function Kit phenotypes, including white coat color, decreased numbers of dermal mast cells, and sterility, indicating that despite its oncogenic activity the mutant form cannot accomplish many activities of the wild-type gene. Kit K641E reproduces the pathology associated with the familial GIST syndrome and thus is an excellent model to study Kit pathway activation, ICC biology, GIST pathogenesis, and preclinical validations of GIST therapies and mechanisms of drug resistance.
Details
- Title: Subtitle
- A knock-in mouse model of gastrointestinal stromal tumor harboring Kit K641E
- Creators
- Brian P RUBIN - Department of Pathology, University of Washington Medical Center, Seattle, Washington, United StatesCristina R ANTONESCU - Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, United StatesJames P SCOTT-BROWNE - Department of Pathology, University of Washington Medical Center, Seattle, Washington, United StatesMelissa L COMSTOCK - Department of Pathology, University of Washington Medical Center, Seattle, Washington, United StatesYansong Gu - Department of Radiation Oncology and Immunology, University of Washington Medical Center, Seattle, Washington, United StatesMunir R TANAS - Department of Pathology, University of Washington Medical Center, Seattle, Washington, United StatesCarol B WARE - Department of Comparative Medicine, University of Washington Medical Center, Seattle, Washington, United StatesJessica WOODELL - Department of Pathology, University of Washington Medical Center, Seattle, Washington, United States
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.65(15), pp.6631-6639
- DOI
- 10.1158/0008-5472.CAN-05-0891
- PMID
- 16061643
- NLM abbreviation
- Cancer Res
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Publisher
- American Association for Cancer Research; Philadelphia, PA
- Language
- English
- Date published
- 2005
- Academic Unit
- Pathology
- Record Identifier
- 9984047979102771
Metrics
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