Presenting Author St. Jude Children’s Research Hospital
NUP98 fusion oncoproteins (FOs) are drivers in pediatric leukemias and many transform hematopoietic cells. Most NUP98 FOs harbor an intrinsically disordered region from NUP98 that is prone to liquid-liquid phase separation (LLPS) in vitro. A predominant class of NUP98 FOs, including NUP98-HOXA9 (NHA9), retains a DNA-binding homeodomain, whereas others harbor other types of DNA- or chromatin-binding domains. NUP98 FOs have long been known to form puncta, but long-standing questions are how nuclear puncta form, and how they drive leukemogenesis. We will discuss our studies of NHA9 condensates, showing that homotypic interactions and different types of heterotypic interactions are required to form nuclear puncta, which are associated with aberrant transcriptional activity and transformation of hematopoietic stem and progenitor cells. We also show that three other leukemia-associated NUP98 FOs form nuclear puncta and transform hematopoietic cells. To extend our findings, we tested ~150 additional fusion oncoproteins associate with a wide range of human cancers for puncta formation in cells. We will discuss our observation that gt;50% of these formed cellular condensates, with this behavior for some linked with aberrant gene expression and cell transformation. Our findings indicate that LLPS is critical for leukemogenesis by NUP98 FOs and likely contributes to oncogenesis driven by many other fusion oncoproteins.
Support or Funding Information
This work is supported by P30 CA021765, U54 CA243124, R01 CA246125, St. Jude Collaborative Research Consortium on Membraneless Organelles, and ALSAC.
