Paired box protein 3–Forkhead box protein O1 fusion protein (PAX3–FOXO1)

PAX3–FOXO1 is a fusion transcription factor created by the t(2;13)(q35;q14) chromosomal translocation, fusing the N-terminal DNA binding domains of PAX3 with the C-terminal transactivation domain of FOXO1[1][2][3]. This fusion protein acts as a potent pioneer transcription factor and reprograms chromatin to drive expression of oncogenic gene signatures in alveolar rhabdomyosarcoma (RMS). It blocks normal differentiation of muscle progenitors and can even induce myogenic programs in non-muscle lineages, underpinning the plasticity and aggressiveness of fusion-positive RMS. While PAX3–FOXO1 is a clear driver and dependency in its disease context, its intrinsically disordered structure and nuclear localization have made it an extremely challenging direct drug target. Current therapeutic approaches focus on disrupting its interaction partners and downstream epigenetic networks critical for its oncogenic activity[1][2][3].

Other names

PAX3–FOXO1 (P3F)PAX3/FKHR (historical, FKHR is an alias for FOXO1)PAX3-FOXO1 fusion protein

For indirect targeting strategies: - Inhibition of transcriptional co-activators (CBP/p300 inhibition impairs PAX3–FOXO1-mediated gene activation) - Inhibition of chromatin remodeling (BRD4 and SMARCA4 inhibition disrupts target gene regulation) - Blocking super-enhancer formation and function [1][2]