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Defining the condensate landscape of fusion oncoproteins

Author

Listed:
  • Swarnendu Tripathi

    (St. Jude Children’s Research Hospital)

  • Hazheen K. Shirnekhi

    (St. Jude Children’s Research Hospital)

  • Scott D. Gorman

    (St. Jude Children’s Research Hospital
    Arrakis Therapeutics)

  • Bappaditya Chandra

    (St. Jude Children’s Research Hospital)

  • David W. Baggett

    (St. Jude Children’s Research Hospital)

  • Cheon-Gil Park

    (St. Jude Children’s Research Hospital)

  • Ramiz Somjee

    (St. Jude Children’s Research Hospital
    Rhodes College
    Washington University School of Medicine)

  • Benjamin Lang

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Seyed Mohammad Hadi Hosseini

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Brittany J. Pioso

    (St. Jude Children’s Research Hospital)

  • Yongsheng Li

    (The University of Texas at Austin)

  • Ilaria Iacobucci

    (St. Jude Children’s Research Hospital)

  • Qingsong Gao

    (St. Jude Children’s Research Hospital)

  • Michael N. Edmonson

    (St. Jude Children’s Research Hospital)

  • Stephen V. Rice

    (St. Jude Children’s Research Hospital)

  • Xin Zhou

    (St. Jude Children’s Research Hospital)

  • John Bollinger

    (St. Jude Children’s Research Hospital)

  • Diana M. Mitrea

    (St. Jude Children’s Research Hospital
    Dewpoint Therapeutics)

  • Michael R. White

    (St. Jude Children’s Research Hospital
    IDEXX Laboratories, Inc.)

  • Daniel J. McGrail

    (Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic
    Lerner Research Institute, Cleveland Clinic)

  • Daniel F. Jarosz

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • S. Stephen Yi

    (The University of Texas at Austin
    The University of Texas at Austin)

  • M. Madan Babu

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Charles G. Mullighan

    (St. Jude Children’s Research Hospital)

  • Jinghui Zhang

    (St. Jude Children’s Research Hospital)

  • Nidhi Sahni

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    Baylor College of Medicine)

  • Richard W. Kriwacki

    (St. Jude Children’s Research Hospital
    University of Tennessee Health Sciences Center)

Abstract

Fusion oncoproteins (FOs) arise from chromosomal translocations in ~17% of cancers and are often oncogenic drivers. Although some FOs can promote oncogenesis by undergoing liquid-liquid phase separation (LLPS) to form aberrant biomolecular condensates, the generality of this phenomenon is unknown. We explored this question by testing 166 FOs in HeLa cells and found that 58% formed condensates. The condensate-forming FOs displayed physicochemical features distinct from those of condensate-negative FOs and segregated into distinct feature-based groups that aligned with their sub-cellular localization and biological function. Using Machine Learning, we developed a predictor of FO condensation behavior, and discovered that 67% of ~3000 additional FOs likely form condensates, with 35% of those predicted to function by altering gene expression. 47% of the predicted condensate-negative FOs were associated with cell signaling functions, suggesting a functional dichotomy between condensate-positive and -negative FOs. Our Datasets and reagents are rich resources to interrogate FO condensation in the future.

Suggested Citation

  • Swarnendu Tripathi & Hazheen K. Shirnekhi & Scott D. Gorman & Bappaditya Chandra & David W. Baggett & Cheon-Gil Park & Ramiz Somjee & Benjamin Lang & Seyed Mohammad Hadi Hosseini & Brittany J. Pioso &, 2023. "Defining the condensate landscape of fusion oncoproteins," Nature Communications, Nature, vol. 14(1), pages 1-25, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41655-2
    DOI: 10.1038/s41467-023-41655-2
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    References listed on IDEAS

    as
    1. Nicolas Stransky & Ethan Cerami & Stefanie Schalm & Joseph L. Kim & Christoph Lengauer, 2014. "The landscape of kinase fusions in cancer," Nature Communications, Nature, vol. 5(1), pages 1-10, December.
    2. Jeong Hyun Ahn & Eric S. Davis & Timothy A. Daugird & Shuai Zhao & Ivana Yoseli Quiroga & Hidetaka Uryu & Jie Li & Aaron J. Storey & Yi-Hsuan Tsai & Daniel P. Keeley & Samuel G. Mackintosh & Ricky D. , 2021. "Phase separation drives aberrant chromatin looping and cancer development," Nature, Nature, vol. 595(7868), pages 591-595, July.
    3. Yanli Cheng & Zhongtian Shen & Yaqi Gao & Feilong Chen & Huisha Xu & Qinling Mo & Xinlei Chu & Chang-liang Peng & Takese T. McKenzie & Bridgitte E. Palacios & Jian Hu & Hao Zhou & Jiafu Long, 2022. "Phase transition and remodeling complex assembly are important for SS18-SSX oncogenic activity in synovial sarcomas," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
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