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


Authors: 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.
Article Title: ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours
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. © 2010 Macmillan Publishers Limited. All rights reserved.
Keywords: signal transduction; controlled study; human tissue; gene translocation; human cell; mutation; dna-binding proteins; nonhuman; animal cell; mouse; animals; mice; animal tissue; cell survival; gene targeting; mus; gastrointestinal stromal tumor; imatinib; stem cell factor; interstitial cell of cajal; gastrointestinal stromal tumors; proto-oncogene proteins c-kit; gene amplification; gene expression; gene expression profiling; tumor markers, biological; animal experiment; animal model; protein stability; cytogenetics; genetic transcription; cancer cell culture; cell line, tumor; pyrimidines; carcinogenesis; cell lineage; transcription factors; cell transformation, neoplastic; oncogenes; gene activation; gene expression regulation, neoplastic; cell transformation; disease progression; genomics; binding site; binding sites; piperazines; mutant proteins; tumor; transcriptome; nih 3t3 cells; enhancer region; enhancer elements, genetic; transcription factor er81; digestive system disorder; interstitial cells of cajal
Journal Title: Nature
Volume: 467
Issue: 7317
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2010-10-14
Start Page: 849
End Page: 853
Language: English
DOI: 10.1038/nature09409
PUBMED: 20927104
PROVIDER: scopus
PMCID: PMC2955195
DOI/URL:
Notes: --- - "Cited By (since 1996): 3" - "Export Date: 20 April 2011" - "CODEN: NATUA" - "Source: Scopus"
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MSK Authors
  1. Charles L Sawyers
    199 Sawyers
  2. Yu Chen
    96 Chen
  3. Cristina R Antonescu
    741 Antonescu
  4. Robert Maki
    215 Maki
  5. Ping Chi
    90 Chi
  6. Tambudzai Shamu
    7 Shamu
  7. Lei Zhang
    184 Zhang