title: Combined experience of six independent laboratories attempting to create an Ewing sarcoma mouse model.
abstract: Ewing sarcoma (ES) involves a tumor-specific chromosomal translocation that produces the EWS-FLI1 protein, which is required for the growth of ES cells both in vitro and in vivo. However, an EWS-FLI1-driven transgenic mouse model is not currently available. Here, we present data from six independent laboratories seeking an alternative approach to express EWS-FLI1 in different murine tissues. We used the Runx2, Col1a2.3, Col1a3.6, Prx1, CAG, Nse, NEFL, Dermo1, P0, Sox9 and Osterix promoters to target EWS-FLI1 or Cre expression. Additional approaches included the induction of an endogenous chromosomal translocation, in utero knock-in, and the injection of Cre-expressing adenovirus to induce EWS-FLI1 expression locally in multiple lineages. Most models resulted in embryonic lethality or developmental defects. EWS-FLI1-induced apoptosis, promoter leakiness, the lack of potential cofactors, and the difficulty of expressing EWS-FLI1 in specific sites were considered the primary reasons for the failed attempts to create a transgenic mouse model of ES.
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Tsion Zewdu
authors.initials: TZ
authors.lastname: Minas
authors.affiliation: Genetics and Biology of Cancers Unit, Institut Curie Research Center, PSL Research University, Île-de-France, Paris, France.|INSERM U830, Institut Curie Research Center, Île-de-France, Paris, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Surdez
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Tahereh
authors.initials: T
authors.lastname: Javaheri
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Howarth
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United States of America.
authors.forename: Hong-Jun
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Jenny
authors.initials: J
authors.lastname: Han
authors.affiliation: Genetics and Biology of Cancers Unit, Institut Curie Research Center, PSL Research University, Île-de-France, Paris, France.|INSERM U830, Institut Curie Research Center, Île-de-France, Paris, France.
authors.forename: Zhi-Yan
authors.initials: ZY
authors.lastname: Han
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sax
authors.affiliation: Department of Medicine, and Genetics and Genome Sciences, University of Connecticut Health Science Center, Farmington, CT, United States of America.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Kream
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Sung-Hyeok
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Haydar
authors.initials: H
authors.lastname: Çelik
authors.affiliation: Genetics and Biology of Cancers Unit, Institut Curie Research Center, PSL Research University, Île-de-France, Paris, France.|INSERM U830, Institut Curie Research Center, Île-de-France, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Tirode
authors.affiliation: Institute of Comparative Molecular Endocrinology (CME), University of Ulm, Ulm, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Tuckermann
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Toretsky
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.|Department of Pathology of Laboratory Animals (UPLA), University of Veterinary Medicine, Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Vienna, Austria.|Children´s Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Kovar
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United States of America.
authors.forename: Sean
authors.initials: S
authors.lastname: Lee
authors.affiliation: Division of Hematology and Oncology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: E Alejandro
authors.initials: EA
authors.lastname: Sweet-Cordero
authors.affiliation: Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.|Medical University of Vienna, Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.affiliation: Genetics and Biology of Cancers Unit, Institut Curie Research Center, PSL Research University, Île-de-France, Paris, France.|INSERM U830, Institut Curie Research Center, Île-de-France, Paris, France.|Unité de génétique somatique, Institut Curie, Île-de-France, Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, United States of America.
authors.forename: Aykut
authors.initials: A
authors.lastname: Üren
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics*; D034802:RNA-Binding Protein EWS / Q000235:genetics*; D012512:Sarcoma, Ewing / Q000235:genetics / Q000473:pathology*
chemical_list: C106031:EWS-FLI fusion protein; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS
keywords: EWS-FLI1; EWS-FLI1 driven transgenic mouse model; Ewing sarcoma