Although, in hpMSCs, overexpression of EWSR1::FLI1 remodels the chromatin landscape by redistributing H3K27me3, in Ewing sarcoma cell lines, depletion of KDM6B—but not KDM6A—exerts its main effects partly by restoring H3K27me3 levels at enhancers. Here, FLI1 is linked to Ewing sarcoma.