EWS-FLI-1 EXPRESSION TRIGGERS A EWING’S SARCOMA INITIATION PROGRAM IN PRIMARY HUMAN MESENCHYMAL STEM CELLS

Abstract

Ewing’s sarcoma family tumors (ESFT) express the EWS-FLI1 fusion gene generated by the chromosomal translocation t(11;22)(q24;q12). Expression of the EWS-FLI-1 fusion protein in a permissive cellular environment is believed to play a key role in ESFT pathogenesis. However, EWS-FLI1 induces growth arrest or apoptosis in differentiated primary cells and the identity of permissive primary human cells that can support its expression and function has until now remained elusive. Here we show that expression of EWS-FLI1 in primary human mesenchymal stem cells (hMSC) is not only stably maintained without inhibiting proliferation, but that it induces a gene expression profile bearing striking similarity to that of ESFT, including genes that are among the highest ESFT discriminators.

Expression of EWS-FLI-1 in MSCs may recapitulate the initial steps of Ewing’s sarcoma development, allowing identification of genes that play an important role early in its pathogenesis. These observations are consistent with our recent findings using mouse mesenchymal progenitor cells and provide compelling evidence that hMSCs are candidate cells of origin of ESFT.