ETS family transcription factors (e.g. ERG, ETV1) are well-established oncogenes involved in recurrent genomic alterations in prostate cancer, Ewing sarcoma and melanoma. Recently, we uncovered an oncogenic role of ETV1 in GIST – one of the most common types of human sarcoma. GIST is primarily defined by activating mutations in the KIT or PDGFRA receptor tyrosine kinases. KIT is highly expressed in the interstitial cells of Cajal (ICCs) – the presumed cell of origin of GIST – as well as in hematopoietic stem cells, melanocytes, mast cells and germ cells. Yet, humans and mice with germline activating KIT mutations exclusively develop ICC hyperplasia and GIST, suggesting that the cellular context is important for mutant KIT-medicated oncogenesis. We have discovered that ETV1 is highly expressed in the subtypes of ICCs sensitive to mutant KIT-mediated transformation, and is required for their development. In addition, ETV1 is universally highly expressed in GISTs and is required for growth and survival of both imatinib-sensitive and –resistant GIST. Transcriptome and global analyses of ETV1-binding sites suggest that ETV1 is a master regulator of an ICC/GIST-specific transcriptome. The ETV1-dependent transcriptome is further regulated by activated KIT which prolongs ETV1 protein stability and cooperates with ETV1 to promote tumorigenesis. These results, unlike other malignancies, suggest that ETV1 is a lineage-specific survival factor in the ICC/GIST lineage and that ETV1 defines the optimal cellular context for mutant KIT-mediated oncogenesis. Here, we propose to further characterize mechanisms of signaling-dependent regulation of ETV1 protein stability, and to discover novel strategies to target ETV1 protein stability and transcriptional activity in imatinib-resistant GIST, using integrative approaches involving biochemistry, cell/molecular biology, genomics and epigenomics, and combined high-throughput RNAi technology with high-complexity gene-signature based readouts. These studies will provide mechanistic insights of ETV1 regulation in GIST pathogenesis and delineate novel therapeutic strategies of ETV1 in GIST and other ETV1-dependent malignancies.