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

A novel study unravels the intricate transcriptional circuitry that governs the onset of alveolar rhabdomyosarcoma (ARMS), a cancer type predominantly linked to the PAX3::FOXO1 (P3F) fusion oncoprotein. Researchers developed a doxycycline-inducible, degradable P3F iPSC-derived ARMS model to dissect the temporal prerequisites of P3F for ARMS cell identity and proliferation.

The findings indicate that while P3F is indispensable for sparking ARMS transformation from precursor cells, its continued presence is not necessary for sustaining proliferation, viability, or RMS-associated transcriptional pathways. Through CUT&RUN, bulk RNA sequencing, and 10X multiome profiling during endothelial-directed differentiation, scientists discovered that P3F swiftly initiates a unique enhancer landscape within two days of activation.

This activation orchestrates the expression of transcriptional circuits driven by specific myogenic and neural transcription factors (TFs), such as MYOD1, PRDM12, and POU4F1 (BRN3A).

The single-cell analysis revealed that these TFs are co-expressed with P3F right from the outset of transformation. Knocking out MYOD1 or POU4F1 disrupts ARMS identity acquisition, without impeding transformation. In contrast, eliminating PRDM12 amplifies P3F expression programs and myogenic differentiation. These discoveries shed light on the uncharted interplay between myogenic and neural transcriptional programs during ARMS initiation.

Moreover, the study demonstrates that P3F instigates a stable oncogenic state that endures even post its removal, thereby offering a framework to investigate P3F-dependent and P3F-independent therapeutic susceptibilities.