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.