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Mithramycin Alters EWS::FLI1 DNA Binding and RNA Polymerase II Processivity to Inhibit Nascent Transcription [RNA-seq]

GSE316978 Homo sapiens Expression profiling by high throughput sequencing 9 samples Submitted 2026/01/22 Platform GPL18573
Summary
Although many DNA binding natural products exert their effects through non-specific mechanisms, a therapeutic opportunity exists for a subset of these compounds that alter the expression or activity of specific driver oncogenes in specific cell contexts. In this study, we integrate CUT&Tag with Global Run-On Sequencing (CUT, Tag, and GRO) to show that the minor groove binding compound, mithramycin (MMA), inhibits the Ewing sarcoma oncogenic driver, the EWS::FLI1 transcription factor. MMA causes either an increase or decrease in EWS::FLI1 binding to chromatin at downstream target response elements to poison nascent transcription. The reversal of EWS::FLI1 activity is limited by non-specific effects of the drug on RNAPII processivity but can be optimized by continuous administration at low concentration to cause more precise reversal of the oncogenic transcriptome and striking Ewing sarcoma xenograft regressions. The activity in vivo is further improved with a less-toxic second-generation analog, AIT-102.
Published in
Mithramycin alters EWS::FLI1 DNA binding and RNA polymerase II processivity to inhibit nascent transcription
Kaufman R, Flores G, Boguslawski EA et al. · Nature communications 2026 · PMID 41698909 · doi:10.1038/s41467-026-69488-9
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Also filed as BioProject PRJNA1405627 and SRA study SRP664762. Searching any of these in the dataset finder brings you back here.

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