TY - JOUR
T1 - ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours
AU - Chi, Ping
AU - Chen, Yu
AU - Zhang, Lei
AU - Guo, Xingyi
AU - Wongvipat, John
AU - Shamu, Tambudzai
AU - Fletcher, Jonathan A.
AU - Dewell, Scott
AU - Maki, Robert G.
AU - Zheng, Deyou
AU - Antonescu, Cristina R.
AU - Allis, C. David
AU - Sawyers, Charles L.
N1 - Funding Information:
Acknowledgements This work was supported in part by the National Cancer Institute (K08CA140946, to Y.C.), (5F32CA130372, to P.C.), (CA47179, to C.R.A. and R.G.M.), (CA148260, toR.G.M.),US National Institute of MentalHealth(R21MH087840,toD.Z.), National Cancer Institute–American Society of Clinical Oncology Cancer Foundation Clinical Investigator Team Leadership Supplemental Award (to R.G.M.), American Society of Clinical Oncology Young Investigator Award (to P.C.), the Doris Duke (to C.L.S.), Charles H Revson (to Y.C.) and Charles A. Dana (to Y.C.) foundations, The Rockefeller University Fund (to C.D.A.), American Cancer Society Mentored Research Scholar GrantCCE-106841 (to C.R.A.),P01CA47179 (to C.R.A.and R.G.M.),theLifeRaft Group (to C.R.A.), the GIST Cancer Research Fund (to C.R.A.), the Shuman Family Fund for GIST Research (to P.C., C.R.A. and R.G.M.), Cycle for Survival (to R.G.M.), Startup Funds from the Albert Einstein College of Medicine (to D.Z.), National Institutes of Health (GM40922, to C.D.A.) and the Starr Cancer Consortium (to P.C., Y.C., C.L.S. and C.D.A.). We thank the International Genomics Consortium for generating ExpO data. We thank G. Wang, P. Iaquinta, and H. Hieronymus for discussions, and especially T. M. Jessell and J. N. Betley for providing and breeding Etv12/2 mice.
PY - 2010/10/14
Y1 - 2010/10/14
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=77957943127&partnerID=8YFLogxK
U2 - 10.1038/nature09409
DO - 10.1038/nature09409
M3 - Article
C2 - 20927104
AN - SCOPUS:77957943127
SN - 0028-0836
VL - 467
SP - 849
EP - 853
JO - Nature
JF - Nature
IS - 7317
ER -