Myogenic and neural transcriptional circuitry determines PAX3::FOXO1 driven initiation of rhabdomyosarcoma

PAX3::FOXO1 rapidly pioneers a new enhancer landscape within two days in a doxycycline-inducible iPSC-derived alveolar rhabdomyosarcoma model, co-activating myogenic and neural TF circuits.

• Why it matters: ARMS initiation by PAX3::FOXO1 is known, but how it establishes tumor cell identity and which transcriptional programs it sustains versus merely initiates is unclear.
• What they did: Using a doxycycline-inducible, degradable PAX3::FOXO1 iPSC-derived ARMS model, the study combined CUT&RUN, bulk RNA-seq, and 10X multiome profiling during endothelial-directed differentiation to map early enhancer and TF activation.
• The result: P3F is essential for initiating transformation, while continued P3F expression is not required for maintaining proliferation, viability, or RMS transcriptional programs; MYOD1 or POU4F1 loss reduces identity acquisition without blocking transformation, and PRDM12 loss enhances P3F programs.

AI summary of the abstract · may contain errors · not medical advice · read the paper.