ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours

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Abstract
Gastroinestinal stromal tumours (GISTs) arise in the interstitial cells of Cajal, cells embedded in the musculature of the gastrointestinal tract where they generate electrical rhythmicity. Chi et al. now show that the transcription factor ETV1 is required for the development of these cells, and also promotes tumour development. The KIT gene, often activated by mutations in GIST, cooperates with ETV1 in the transformation of interstitial cells of Cajal, in part by promoting ETV1 stabilization. ETV1 seems to be present in high levels in all GISTs, making it a candidate diagnostic biomarker, and ETV1 blockers may prove useful against drug-resistant GIST. Gastrointestinal stromal tumours (GIST) are believed to arise in interstitial cells of Cajal (ICC). These authors show that the transcription factor ETV1 is required for ICC development and promotes the development of GIST. KIT, which is often activated by mutations in GIST, cooperates with ETV1 in the transformation of ICCs, in part by promoting ETV1 stabilization. Thus, a normal developmental lineage factor is switched into a tumour-promoting factor by a cooperating oncogene. Gastrointestinal stromal tumour (GIST) is the most common human sarcoma and is primarily defined by activating mutations in the KIT or PDGFRA receptor tyrosine kinases1,2. KIT is highly expressed in interstitial cells of Cajal (ICCs)—the presumed cell of origin for GIST—as well as in haematopoietic stem cells, melanocytes, mast cells and germ cells2,3. Yet, families harbouring germline activating KIT mutations and mice with knock-in Kit mutations almost exclusively develop ICC hyperplasia and GIST4,5,6,7, suggesting that the cellular context is important for KIT to mediate oncogenesis. Here we show that the ETS family member ETV1 is highly expressed in the subtypes of ICCs sensitive to oncogenic KIT mediated transformation8, and is required for their development. In addition, ETV1 is universally highly expressed in GISTs and is required for growth of imatinib-sensitive and resistant GIST cell lines. Transcriptome profiling and global analyses of ETV1-binding sites suggest that ETV1 is a master regulator of an ICC-GIST-specific transcription network mainly through enhancer binding. The ETV1 transcriptional program is further regulated by activated KIT, which prolongs ETV1 protein stability and cooperates with ETV1 to promote tumorigenesis. We propose that GIST arises from ICCs with high levels of endogenous ETV1 expression that, when coupled with an activating KIT mutation, drives an oncogenic ETS transcriptional program. This differs from other ETS-dependent tumours such as prostate cancer, melanoma and Ewing sarcoma where genomic translocation or amplification drives aberrant ETS expression9,10,11. It also represents a novel mechanism of oncogenic transcription factor activation.