Abstract
Ewing's sarcoma family tumors (ESFT) express the EWS-FLI-1 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-FLI-1 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-FLI-1 in human mesenchymal stem cells (hMSC) is not only stably maintained without inhibiting proliferation but also 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 hMSCs may recapitulate the initial steps of Ewing's sarcoma development, allowing identification of genes that play an important role early in its pathogenesis. Among relevant candidate transcripts induced by EWS-FLI-1 in hMSCs, we found the polycomb group gene EZH2, which we show to play a critical role in Ewing's sarcoma growth. 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.
Highlights
IntroductionEwing’s sarcoma is the second most common bone malignancy in children and young adults with a peak incidence between the ages of 14 and 20 years
Ewing’s sarcoma is the second most common bone malignancy in children and young adults with a peak incidence between the ages of 14 and 20 years. It is associated with specific chromosomal translocations that lead to the formation of fusion genes encoding proteins composed of the transactivation domain of EWS and the DNA binding domain (DBD) of one of five ETS family transcription factors, including FLI1, ERG, ETV1, ETV4, and FEV
The highly discriminating ability of the hMSCEWS-FLI-1 gene expression profile for Ewing’s sarcoma family tumors (ESFT) was further confirmed by another study, which assessed the transcriptome of a broad range of mesenchymal tumors and identified the CALCB, MAPT, and PRKCB1 genes as prominent Ewing’s sarcoma discriminators [32], all of which we found to be induced in hMSCEWS-FLI-1 (Table 1; Supplementary data 2)
Summary
Ewing’s sarcoma is the second most common bone malignancy in children and young adults with a peak incidence between the ages of 14 and 20 years. It is associated with specific chromosomal translocations that lead to the formation of fusion genes encoding proteins composed of the transactivation domain of EWS and the DNA binding domain (DBD) of one of five ETS family transcription factors, including FLI1, ERG, ETV1, ETV4, and FEV. Introduction of EWS-FLI-1 into heterologous cells and fusion protein expression knockdown in ESFT cell lines have led to the identification of several candidate EWS-FLI-1 target genes that may be implicated in transformation and/or tumor progression Full elucidation of ESFT pathogenesis requires understanding of the tumor initiating program induced by EWS-FLI-1 and identification of primary target cells that are permissive for its expression
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