Oncogenic biomolecular condensation in NUP98-fusion leukemia

Biomolecular condensates are membrane-less subcellular structures that dynamically coordinate compartmentalization of macromolecules. In the nucleus, they orchestrate critical biological processes including chromatin organization and transcription. Their formation is regulated by proteins with intrinsically disordered regions (IDRs) that can undergo liquid-liquid phase separation. Many fusion proteins arising from chromosomal aberrations are strong oncogenic drivers. In childhood acute myeloid leukemia (AML), an aggressive blood cancer, sequences of IDR-containing proteins are frequently fused to transcriptional regulators or epigenetic modulators. The NUP98 genes are the most abundant IDR-containing partners in childhood AML gene fusions and NUP98-fusion-AML has survival rates among the lowest of any blood cancers. We hypothesize that IDR-containing NUP98-fusion oncoproteins alter the genesis, composition and function of nuclear biomolecular condensates to induce cancer, and propose that oncogenic biomolecular condensation can be exploited to target cancer. Dynamics of NUP98-fusion-containing condensates will be characterized by state-of-the-art imaging approaches in AML cells. To delineate oncogenic mechanisms in NUP98-fusion-driven AML we will combine models of ligand-induced NUP98-fusion protein degradation with newly established global approaches that enable the time-resolved investigation of the dynamics of biomolecular condensates. To identify actionable target candidates, datasets will be functionally annotated through readily available genome-scale CRISPR/Cas9 knockout-screening data followed by extensive validation. Finally, we will develop strategies for peptide-mediated targeting of Nup98-fusion-dependent biomolecular condensation. Through a complementary array of technologies we will shed light on the functional involvement of oncogene-induced, altered biomolecular condensation in cancer. the work will contribute to an understanding of how molecular alterations functionally integrate into larger cellular structures to execute oncogenic programs. Novel molecular mechanisms might have potential for clinical translation with the vision of directly improving prognostic and therapeutic strategies for cancer patients by targeting aberrant biomolecular condensation.

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