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      ETV1 is a lineage-specific survival factor in GIST and cooperates with KIT in oncogenesis

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          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 1, 2. KIT is highly expressed in interstitial cells of Cajal (ICCs)—the presumed cell of origin for GIST—as well as in hematopoietic stem cells, melanocytes, mast cells and germ cells 2, 3. Yet, families harbouring germline activating KIT mutations and mice with knock-in Kit mutations almost exclusively develop ICC hyperplasia and GIST 47, suggesting that the cellular context is important for KIT to mediated oncogenesis. Here we show that the ETS family member ETV1 is 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 tumourigenesis. 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 transcription 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 911 and represents a novel mechanism of oncogenic transcription factor activation.

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          Most cited references 17

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          ChIP-seq accurately predicts tissue-specific activity of enhancers.

          A major yet unresolved quest in decoding the human genome is the identification of the regulatory sequences that control the spatial and temporal expression of genes. Distant-acting transcriptional enhancers are particularly challenging to uncover because they are scattered among the vast non-coding portion of the genome. Evolutionary sequence constraint can facilitate the discovery of enhancers, but fails to predict when and where they are active in vivo. Here we present the results of chromatin immunoprecipitation with the enhancer-associated protein p300 followed by massively parallel sequencing, and map several thousand in vivo binding sites of p300 in mouse embryonic forebrain, midbrain and limb tissue. We tested 86 of these sequences in a transgenic mouse assay, which in nearly all cases demonstrated reproducible enhancer activity in the tissues that were predicted by p300 binding. Our results indicate that in vivo mapping of p300 binding is a highly accurate means for identifying enhancers and their associated activities, and suggest that such data sets will be useful to study the role of tissue-specific enhancers in human biology and disease on a genome-wide scale.
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            PDGFRA activating mutations in gastrointestinal stromal tumors.

            Most gastrointestinal stromal tumors (GISTs) have activating mutations in the KIT receptor tyrosine kinase, and most patients with GISTs respond well to Gleevec, which inhibits KIT kinase activity. Here we show that approximately 35% (14 of 40) of GISTs lacking KIT mutations have intragenic activation mutations in the related receptor tyrosine kinase, platelet-derived growth factor receptor alpha (PDGFRA). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Thus, KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.
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              Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal.

              The interstitial cells of Cajal (ICC) form a complex cell network within the gastrointestinal tract wall where they function as a pacemaker system. Expression of the kit proto-oncogene is essential for the development of this system. The aim of our study was to examine the hypothesis that gastrointestinal stromal tumors differentiate toward cells with an ICC phenotype. Ultrastructurally, 58 stromal tumors were characterized and found to share many features with ICC. Seventy-eight stromal tumors were immunophenotyped, particularly with regard to the kit receptor. All 78 tumors revealed strong, homogeneous immunoreactivity for the kit receptor as did ICC of adjacent and control gastrointestinal walls. Focal hyperplasia and hypertrophy of kit receptor positive cells were also observed in the gastrointestinal wall adjacent to the tumors. CD34 immunoreactivity observed in interstitial cells surrounding Auerbach's ganglia suggests that a subpopulation of ICC is CD34 positive and may explain why 56 of 78 stromal tumors were CD34 positive. Thirty control tumors, including gastrointestinal leiomyomas and leiomyosarcomas, were all negative for the kit receptor. We conclude that gastrointestinal stromal tumors show striking morphological and immunophenotypic similarities with ICC and that they may originate from stem cells that differentiate toward a pacemaker cell phenotype. We propose that the noncommittal name "gastrointestinal stromal tumor" be replaced by gastrointestinal pacemaker cell tumor.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                3 August 2010
                3 October 2010
                14 October 2010
                14 April 2011
                : 467
                : 7317
                : 849-853
                Affiliations
                [1 ] Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
                [2 ] Laboratory of Chromatin Biology & Epigenetics, The Rockefeller University, New York, New York, USA
                [3 ] Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
                [4 ] Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
                [5 ] Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA
                [6 ] Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
                [7 ] Genomics Resource Center, The Rockefeller University, New York, New York, USA
                [8 ] Departments of Genetics and Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA
                [9 ] Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York, USA
                Author notes
                Correspondence to: Charles L. Sawyers 3 and C. David Allis 2 Correspondence and requests for materials should be addressed to C.L.S. ( sawyersc@ 123456mskcc.org ) or C.D.A. ( alliscd@ 123456rockefeller.edu )
                [10]

                These authors contributed equally to this work

                [11]

                These authors contributed equally to this work

                Article
                nihpa225624
                10.1038/nature09409
                2955195
                20927104

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funding
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of Mental Health : NIMH
                Award ID: RC2 CA148260-02 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of Mental Health : NIMH
                Award ID: R21 MH087840-01 ||MH
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of Mental Health : NIMH
                Award ID: P01 CA047179-169002 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of Mental Health : NIMH
                Award ID: K08 CA140946-02 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of Mental Health : NIMH
                Award ID: F32 CA130372-02 ||CA
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