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

Research output: Contribution to journalArticle

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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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Interstitial Cells of Cajal
Gastrointestinal Stromal Tumors
Survival
Mutation
Carcinogenesis
Ewing's Sarcoma
Protein Stability
Melanocytes
Gene Expression Profiling
Stromal Cells
Hematopoietic Stem Cells
Tumor Cell Line
Mast Cells
Sarcoma
Transcriptional Activation
Hyperplasia
Melanoma
Prostatic Neoplasms
Transcription Factors
Binding Sites

ASJC Scopus subject areas

  • General

Cite this

Chi, P., Chen, Y., Zhang, L., Guo, X., Wongvipat, J., Shamu, T., ... 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

ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. / Chi, Ping; Chen, Yu; Zhang, Lei; Guo, Xingyi; Wongvipat, John; Shamu, Tambudzai; Fletcher, Jonathan A.; Dewell, Scott; Maki, Robert G.; Zheng, Deyou; Antonescu, Cristina R.; Allis, C. David; Sawyers, Charles L.

In: Nature, Vol. 467, No. 7317, 14.10.2010, p. 849-853.

Research output: Contribution to journalArticle

Chi, P, Chen, Y, Zhang, L, Guo, X, Wongvipat, J, Shamu, T, Fletcher, JA, Dewell, S, Maki, RG, Zheng, D, Antonescu, CR, Allis, CD & Sawyers, CL 2010, 'ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours', Nature, vol. 467, no. 7317, pp. 849-853. https://doi.org/10.1038/nature09409
Chi P, Chen Y, Zhang L, Guo X, Wongvipat J, Shamu T et al. ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Nature. 2010 Oct 14;467(7317):849-853. https://doi.org/10.1038/nature09409
Chi, Ping ; Chen, Yu ; Zhang, Lei ; Guo, Xingyi ; Wongvipat, John ; Shamu, Tambudzai ; Fletcher, Jonathan A. ; Dewell, Scott ; Maki, Robert G. ; Zheng, Deyou ; Antonescu, Cristina R. ; Allis, C. David ; Sawyers, Charles L. / ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. In: Nature. 2010 ; Vol. 467, No. 7317. pp. 849-853.
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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.",
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