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Somatic chromosomal translocation between Ewsr1 and Fli1 loci leads to dilated cardiomyopathy in a mouse model.

Abstract
A mouse model that recapitulates the human Ewing's sarcoma-specific chromosomal translocation was generated utilizing the Cre/loxP-mediated recombination technique. A cross between Ewsr1-loxP and Fli1-loxP mice and expression of ubiquitous Cre recombinase induced a specific translocation between Ewsr1 and Fli1 loci in systemic organs of both adult mice and embryos. As a result Ewsr1-Fli1 fusion transcripts were expressed, suggesting a functional Ews-Fli1 protein might be synthesized in vivo. However, by two years of age, none of the Ewsr1-loxP/Fli1-loxP/CAG-Cre (EFCC) mice developed any malignancies, including Ewing-like small round cell sarcoma. Unexpectedly, all the EFCC mice suffered from dilated cardiomyopathy and died of chronic cardiac failure. Genetic recombination between Ewsr1 and Fli1 was confirmed in the myocardial tissue and apoptotic cell death of cardiac myocytes was observed at significantly higher frequency in EFCC mice. Moreover, expression of Ews-Fli1 in the cultured cardiac myocytes induced apoptosis. Collectively, these results indicated that ectopic expression of the Ews-Fli1 oncogene stimulated apoptotic signals, and suggested an important relationship between oncogenic signals and cellular context in the cell-of-origin of Ewing's sarcoma.
AuthorsMiwa Tanaka, Shuichi Yamaguchi, Yukari Yamazaki, Hideyuki Kinoshita, Koichiro Kuwahara, Kazuwa Nakao, Patrick Y Jay, Tetsuo Noda, Takuro Nakamura
JournalScientific reports (Sci Rep) Vol. 5 Pg. 7826 (Jan 16 2015) ISSN: 2045-2322 [Electronic] England
PMID25591392 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • EWS-FLI fusion protein
  • Fli1 protein, mouse
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • RNA-Binding Protein EWS
Topics
  • Animals
  • Apoptosis
  • Base Sequence
  • Cardiomyopathy, Dilated (metabolism, mortality, pathology)
  • Cells, Cultured
  • Chromosomes
  • Disease Models, Animal
  • Gene Targeting
  • Genetic Loci
  • Liver (pathology)
  • Mice
  • Mice, Inbred ICR
  • Myocytes, Cardiac (cytology, metabolism)
  • Oncogene Proteins, Fusion (chemistry, genetics)
  • Proto-Oncogene Protein c-fli-1 (chemistry, genetics)
  • RNA-Binding Protein EWS (chemistry, genetics)
  • Sequence Analysis, DNA
  • Survival Rate
  • Translocation, Genetic

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