EWS-FLI1 in embryonic hMSCs induces DNA damage and Ewing sarcoma tumorigenesis [ChIP-seq]

Ewing sarcoma (ES) is an aggressive bone and soft tissue neoplasm, unique to humans, characterized by EWSR1/ETS rearrangements and whose cellular origin remains unclear. Expression of EWS-FLI1 in pediatric human mesenchymal stem cells (hMSCs) induced a transcriptional profile more resembling ES than its expression in adult hMSCs, but did not confer tumorigenic capacity. We have isolated human mesenchymal stem-like cells (hMSLCs) from experimental human embryonic stem cell (hESC)-derived teratomas. EWS-FLI1 expression in hMSLCs results in the acquisition of an ES signature through its preferential binding to microsatellites of intergenic and intronic regions. In hMSLCs, EWS-FLI1 directly regulates BRCA1 expression, although oncogene-expressing cells show defects in DNA damage repair (DDR). Xenografting in mice of EWS-FLI1-transduced hMSLCs resulted in the formation of tumors expressing characteristic ES markers. In summary, EWS-FLI1 enforces an aberrant transcriptome and endows in vivo transforming capacity when expressed in an undifferentiated early embryonic hMSC. Our approach represents an innovative experimental method for understanding critical aspects of the biology of developmental tumors, from leukemia to sarcomas, in which few (even single) genetic alterations are able to transform a fetal stem cell.