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Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation.

Bappaditya Chandra¹, Nicole L Michmerhuizen², Hazheen K Shirnekhi¹

¹Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Cancer Discovery

|December 14, 2021

Summary

Nuclear puncta formed by NUP98 fusion oncoproteins (FOs) drive pediatric leukemia. Liquid-liquid phase separation (LLPS) mechanisms control these puncta, impacting transcriptional activity and transforming hematopoietic cells, highlighting LLPS

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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.