Imatinib resistance and microcytic erythrocytosis in a KitV558Δ;T669I/+ gatekeeper-mutant mouse model of gastrointestinal stromal tumor.

ABSTRACT: Most gastrointestinal stromal tumors (GISTs) harbor a gain-of-function mutation in the Kit receptor. GIST patients treated with the tyrosine kinase inhibitor imatinib frequently develop imatinib resistance as a result of second-site Kit mutations. To investigate the consequences of second-site Kit mutations on GIST development and imatinib sensitivity, we engineered a mouse model carrying in the endogenous Kit locus both the Kit(V558Δ) mutation found in a familial case of GIST and the Kit(T669I) (human KIT(T670I)) "gatekeeper" mutation found in imatinib-resistant GIST patients. Similar to Kit(V558/+) mice, Kit(V558;T669I/+) mice developed gastric and colonic interstitial cell of Cajal hyperplasia as well as cecal GIST. In contrast to the single-mutant Kit(V558/+) control mice, treatment of

SUBMITTER: Bosbach B 

PROVIDER: S-EPMC3427109 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature