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

Ping Chi, Yu Chen, Lei Zhang, Xingyi Guo, John Wongvipat, Tambudzai Shamu, Jonathan A. Fletcher, Scott Dewell, Robert G. Maki, Deyou Zheng, Cristina R. Antonescu, C. David Allis, Charles L. Sawyers

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187 Scopus citations

Abstract

Gastrointestinal stromal tumour (GIST) is the most common human sarcoma and is primarily defined by activating mutations in the KITor PDGFRAreceptor tyrosine kinases1,2. KITis 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 GIST4-7, suggesting that the cellular context is important for KIT to mediate oncogenesis. Here we show that the ETSfamily member ETV1is highly expressed in the subtypes of ICCs sensitive to oncogenic KIT mediated transformation 8, 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 ETSexpression 9-11. It also represents a novel mechanism of oncogenic transcription factor activation.

Original languageEnglish (US)
Pages (from-to)849-853
Number of pages5
JournalNature
Volume467
Issue number7317
DOIs
StatePublished - Oct 14 2010

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    Chi, P., Chen, Y., Zhang, L., Guo, X., Wongvipat, J., Shamu, T., Fletcher, J. A., Dewell, S., Maki, R. G., Zheng, D., Antonescu, C. R., Allis, C. D., & Sawyers, C. L. (2010). ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Nature, 467(7317), 849-853. https://doi.org/10.1038/nature09409