Abstract Ewing sarcoma (ES) is an aggressive bone and soft tissue neoplasm characterized by EWSR: : ETS rearrangements whose cellular origin remains unclear. EWS: : FLI1 expression in human pediatric mesenchymal stem cells (MSCs) induces a transcriptional response distinct from that of human adult MSCs, but fails to form tumors. We have generated MSCs from experimental teratomas out of human embryonic stem cells. EWS: : FLI1 expression in these human embryonic mesenchymal stem cells (heMSCs) results in the acquisition of an ES transcriptome, with the oncogene not preferentially binding to promoters, but to intronic -with 10 CA dinucleotides- and intergenic microsatellites with GGAA repeats. In heMSCs, EWS: : FLI1 directly regulates BRCA1 expression, even though EWS: : FLI1-expressing cells show defects in DNA damage repair. Xenografting of EWS: : FLI1-transduced heMSCs resulted 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. Citation Format: Inmaculada Hernandez, Irene cuervas, Estela prada, Angel Raya, Jaume Mora. EWS: : FLI1 Expression in Human Embryonic Mesenchymal Stem Cells Leads to Transcriptional Reprograming, Defective DNA Damage Repair and Ewing Sarcoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Discovery and Innovation in Pediatric Cancer— From Biology to Breakthrough Therapies; 2025 Sep 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₂): Abstract nr A035-PR003.
Hernández et al. (Thu,) studied this question.