Phase Separation Mediates NUP98 Fusion Oncoprotein Leukemic Transformation

  • Bappaditya Chandra
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Nicole L. Michmerhuizen
    2Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Hazheen K. Shirnekhi
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Swarnendu Tripathi
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Brittany J. Pioso
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • David W. Baggett
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Diana M. Mitrea
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Ilaria Iacobucci
    2Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Michael R. White
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Jingjing Chen
    3Integrated Biomedical Sciences Program, the University of Tennessee Health Science Center, Memphis, Tennessee.
  • Cheon-Gil Park
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Huiyun Wu
    5Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Stanley Pounds
    5Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Anna Medyukhina
    6Center for Bioimage Informatics, St. Jude Children's Research Hospital Memphis, Tennessee.
  • Khaled Khairy
    6Center for Bioimage Informatics, St. Jude Children's Research Hospital Memphis, Tennessee.
  • Qingsong Gao
    2Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Chunxu Qu
    2Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Sherif Abdelhamed
    2Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Scott D. Gorman
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Simranjot Bawa
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Carolyn Maslanka
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Swati Kinger
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Priyanka Dogra
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Mylene C. Ferrolino
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Danika Di Giacomo
    8Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
  • Cristina Mecucci
    8Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
  • Jeffery M. Klco
    2Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Charles G. Mullighan
    2Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Richard W. Kriwacki
    1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.

抄録

<jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>NUP98 fusion oncoproteins (FO) 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. Here we studied NHA9 condensates and show 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 additional leukemia-associated NUP98 FOs (NUP98–PRRX1, NUP98–KDM5A, and NUP98–LNP1) form nuclear puncta and transform hematopoietic cells. These findings indicate that LLPS is critical for leukemogenesis by NUP98 FOs.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>We show that homotypic and heterotypic mechanisms of LLPS control NUP98–HOXA9 puncta formation, modulating transcriptional activity and transforming hematopoietic cells. Importantly, these mechanisms are generalizable to other NUP98 FOs that share similar domain structures. These findings address long-standing questions on how nuclear puncta form and their link to leukemogenesis.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 873</jats:p> </jats:sec>

収録刊行物

  • Cancer Discovery

    Cancer Discovery 12 (4), 1152-1169, 2021-12-13

    American Association for Cancer Research (AACR)

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