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. (October 2010) ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Nature, 467 (7317). pp. 849-53. ISSN 1476-4687 (Electronic)0028-0836 (Linking)
Abstract
Gastrointestinal stromal tumour (GIST) is the most common human sarcoma and is primarily defined by activating mutations in the KIT or PDGFRA receptor tyrosine kinases. 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 cells. Yet, families harbouring germline activating KIT mutations and mice with knock-in Kit mutations almost exclusively develop ICC hyperplasia and GIST, 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 transformation, 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 expression. It also represents a novel mechanism of oncogenic transcription factor activation.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Animals Benzamides Binding Sites Biomarkers, Tumor/genetics/metabolism Cell Line, Tumor *Cell Lineage Cell Survival/drug effects *Cell Transformation, Neoplastic DNA-Binding Proteins/antagonists & inhibitors/genetics/*metabolism Disease Progression Enhancer Elements, Genetic/genetics Gastrointestinal Stromal Tumors/*metabolism/*pathology Gene Expression Profiling Gene Expression Regulation, Neoplastic/genetics Humans Imatinib Mesylate Interstitial Cells of Cajal/metabolism/pathology Mice Mutant Proteins/genetics/metabolism Mutation NIH 3T3 Cells Oncogenes/genetics/*physiology Piperazines/pharmacology Protein Stability Proto-Oncogene Proteins c-kit/genetics/*metabolism Pyrimidines/pharmacology Signal Transduction Transcription Factors/antagonists & inhibitors/genetics/*metabolism |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > DNA binding protein diseases & disorders > cancer > cancer types > gastrointestinal stromal tumors bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor |
| CSHL Authors: | |
| Communities: | CSHL labs > Maki lab |
| Depositing User: | Matt Covey |
| Date: | 14 October 2010 |
| Date Deposited: | 25 Oct 2016 16:51 |
| Last Modified: | 25 Oct 2016 16:51 |
| PMCID: | PMC2955195 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/33705 |
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