The presence of KDM6A and KDM6B demethylases at GGAA single and repeat motifs in transformed cells, along with the detrimental effect of their KO on the transcriptional activation of EWSR1::FLI1 targets—concomitant with a reduction in tumor volume—supports their needed role at these positions for maintaining an active transcriptional state. Here, KDM6B is linked to neoplasm.