Biomolecular condensation of NUP98 fusion proteins drives leukemogenic gene expression

A mass spectrometry-based approach is used to investigate the mechanisms by which different NUP98 fusion proteins cause leukemia, revealing that the fusion proteins share common interactors and alter the composition of nuclear condensates. NUP98 fusion proteins cause leukemia via unknown molecular mechanisms. All NUP98 fusion proteins share an intrinsically disordered region (IDR) in the NUP98 N terminus, featuring repeats of phenylalanine-glycine (FG), and C-terminal fusion partners often function in gene control. We investigated whether mechanisms of oncogenic transformation by NUP98 fusion proteins are hardwired in their protein interactomes. Affinity purification coupled to mass spectrometry (MS) and confocal imaging of five NUP98 fusion proteins expressed in human leukemia cells revealed that shared interactors were enriched for proteins involved in biomolecular condensation and that they colocalized with NUP98 fusion proteins in nuclear puncta. We developed biotinylated isoxazole-mediated condensome MS (biCon-MS) to show that NUP98 fusion proteins alter the global composition of biomolecular condensates. An artificial FG-repeat-containing fusion protein phenocopied the nuclear localization patterns of NUP98 fusion proteins and their capability to drive oncogenic gene expression programs. Thus, we propose that IDR-containing fusion proteins combine biomolecular condensation with transcriptional control to induce cancer.

Automated summary

Mass spectrometry-based approach reveals NUP98 fusion proteins share common interactors and alter nuclear condensates composition. Mechanisms of oncogenic transformation by these fusion proteins may be hardwired in their protein interactomes. Fusion proteins combine biomolecular condensation with transcriptional control to induce cancer.