In a recent study, Wang and colleagues reported that a significant fraction of cancer-associated fusion proteins display a common structural topology, including an N-terminal phase separation-prone region (PS) from one parent protein and a C-terminal DNA-binding domain (DBD) from the other. This is reminiscent of the structural topology of transcription factors and led to the hypothesis that the PS-DBD fusions form aberrant transcriptional condensates through phase separation, which was supported through transcriptomic data analysis and cellular condensate assays. The authors developed a high-throughput screen based upon time-lapse, high-content imaging to identify 114 compounds that dissolved condensates formed by a chromatin-dissociated mutant of FUS::ERG (FUS::ERGmut). One of these compounds, LY2835219, was shown to dissolve FUS::ERGmut condensates by promoting lysosome formation and was also active against condensates formed by other PS-DBD fusions, including EWS::FLI1. Finally, condensate dissolution by LY2835219 was shown to reverse aberrant gene expression driven by EWS::FLI1, although how this compound specifically marshals lysosomes to target some PS-DBD fusions and not other condensate-forming proteins remains elusive. This work not only highlights likely roles for aberrant condensate formation in the oncogenic function of PS-DBD fusions, but also provides proof of principle for mechanistically unbiased screening to identify compounds that modulate fusion protein-driven condensates and their oncogenic functions.

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