EWS::FLI1 expression in human embryonic mesenchymal stem cells leads to transcriptional reprograming, defective DNA damage repair and Ewing sarcoma

Oct 24, 2025Nature communications

EWS::FLI1 gene activity in early human stem cells causes changes in gene expression, poor DNA repair, and Ewing sarcoma

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Abstract

expression in leads to the development of tumors expressing characteristic markers.

EWS::FLI1 induces a distinct transcriptional response in human embryonic mesenchymal stem cells compared to other types of stem cells.
The oncogene binds predominantly to intronic and intergenic microsatellites rather than directly to gene promoters.
EWS::FLI1 directly regulates the expression of the DNA repair protein BRCA1 in these cells.
Cells expressing EWS::FLI1 exhibit DNA damage despite the regulation of BRCA1.
Tumors derived from EWS::FLI1-transduced human embryonic mesenchymal stem cells display markers characteristic of Ewing sarcoma.

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(ES) is an aggressive bone and soft tissue neoplasm characterized by EWSR::ETS rearrangements whose cellular origin remains unclear. expression in human pediatric mesenchymal stem cells (MSCs) induces a transcriptional response distinct from that of human adult MSCs, but fails to form tumors. Here we show that EWS::FLI1 expression in (heMSCs) results in the acquisition of an ES transcriptome, with the oncogene not preferentially binding to gene promoters, but to intronic and intergenic microsatellites. In heMSCs, EWS::FLI1 directly regulates the expression of the DNA repair protein BRCA1, although cells expressing EWS::FLI1 show DNA damage. Xenografting of EWS::FLI1-transduced heMSCs results in the formation of tumors expressing characteristic ES markers. In summary, we show that EWS::FLI1 enforces an aberrant transcriptome and solely is able to endow transforming capacity when expressed in undifferentiated, early heMSCs.

Key numbers

3836

Differentially Expressed Genes

Number of genes showing significant expression changes in expressing .

2204

Up-Regulated Genes

Count of genes that are up-regulated following expression.

1632

Down-Regulated Genes

Count of genes that are down-regulated in expressing .

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EWS::FLI1 expression in human embryonic mesenchymal stem cells leads to transcriptional reprograming, defective DNA damage repair and Ewing sarcoma

Abstract

Key numbers

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