ETV1-Positive Cells Give Rise to -Mutant Gastrointestinal Stromal Tumors.

Gastrointestinal stromal tumor (GIST) is the most common subtype of sarcoma. Despite clinical advances in the treatment of -mutant GIST, similar progress against wild-type GIST, including mutant BRAF-driven tumors, has been limited by a lack of model systems. ETV1 is a master regulator in the intestinal cells of Cajal (ICC), thought to be the cells of origin of GIST. Here, we present a model in which the ETV1 promoter is used to specifically and inducibly drive Cre recombinase in ICC as a strategy to study GIST pathogenesis. Using a conditional allele for , a mutation observed in clinical cases of GIST, we observed that activation was sufficient to drive ICC hyperplasia but not GIST tumorigenesis. In contrast, combining activation with loss was sufficient to drive both ICC hyperplasia and formation of multifocal GIST-like tumors in the mouse gastrointestinal tract with 100% penetrance. This mouse model of sporadic GIST model was amenable to therapeutic intervention, and it recapitulated clinical responses to RAF inhibition seen in human GIST. Our work offers a useful model of human sporadic forms of -mutant GIST to help unravel its pathogenesis and therapeutic response to novel experimental agents. .