Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation

Area of Science:

• Molecular Biology
• Cancer Biology
• Hematopoiesis

Background:

• NUP98 fusion oncoproteins (FOs) are key drivers in pediatric leukemias, transforming hematopoietic cells.
• These oncoproteins often contain an intrinsically disordered region from NUP98, promoting liquid-liquid phase separation (LLPS) in vitro.
• NUP98 FOs are known to form nuclear puncta, but the mechanisms and leukemogenic role remain unclear.

Purpose of the Study:

• To investigate the mechanisms of nuclear puncta formation by NUP98-HOXA9 (NHA9) and its role in leukemogenesis.
• To determine if these mechanisms are applicable to other leukemia-associated NUP98 FOs.
• To elucidate the link between LLPS, nuclear puncta, and the transformation of hematopoietic stem and progenitor cells.

Main Methods:

• Studied NHA9 condensates to identify factors involved in nuclear puncta formation.
• Investigated homotypic and heterotypic interaction mechanisms driving LLPS.
• Assessed the impact of puncta formation on transcriptional activity and hematopoietic cell transformation for multiple NUP98 FOs.

Main Results:

• Homotypic and heterotypic interactions are essential for forming NUP98-HOXA9 nuclear puncta.
• These puncta are associated with aberrant transcriptional activity and the transformation of hematopoietic stem and progenitor cells.
• Three other NUP98 FOs (NUP98-PRRX1, NUP98-KDM5A, NUP98-LNP1) also form nuclear puncta and transform hematopoietic cells.

Conclusions:

• Liquid-liquid phase separation (LLPS) is a critical mechanism driving leukemogenesis by NUP98 fusion oncoproteins.
• The identified mechanisms of LLPS-driven puncta formation are generalizable to various NUP98 FOs.
• This study clarifies how nuclear puncta form and contribute to the development of leukemia.