Fusion-positive rhabdomyosarcoma oncofusions share a common interactome

The sole reoccurring oncogenic mutation in the pediatric cancer of fusion-positive rhabdomyosarcoma is a reciprocal translocation giving rise to a transcriptional oncofusion comprised of the N-terminus of the PAX3 transcription factor encoding DNA-binding domains fused in-frame to the C-terminus of the FOXO1 transcription factor encoding a transactivation domain. However, a host of new translocations have been detected in this cancer that are known or predicted to encode a protein comprised of the same PAX3 or its paralog PAX7 N-terminus, but with very different C-terminal fusion partners. How such different oncofusions cause the identical cancer was unknown. Here we show that these oncofusions are functionally interchangeable and engage a common interactome of proteins and activate a core shared transcriptional program. Interestingly, this common interactome contains the C-terminal fusion partners or their paralogs of all tested oncofusions, as well as the C-terminal fusion partner of a novel oncofusion. We thus suggest that oncofusions originate in rhabdomyosarcoma from the same DNA-binding domain fused to proteins within a common interactome, which in turn engages a core set of genes giving rise to this cancer.