Defining the condensate landscape of fusion oncoproteins

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, Yongsheng Li, Ilaria Iacobucci, Qingsong Gao, Michael N. Edmonson, Stephen V. Rice, Xin Zhou, John Bollinger, Diana M. Mitrea, Michael R. White, Daniel J. McGrail, Daniel F. Jarosz, S. Stephen Yi, M. Madan Babu, Charles G. Mullighan, Jinghui Zhang, Nidhi Sahni and Richard W. Kriwacki ()
Additional contact information
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
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
Benjamin Lang: St. Jude Children’s Research Hospital
Seyed Mohammad Hadi Hosseini: 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
Michael R. White: St. Jude Children’s Research Hospital
Daniel J. McGrail: Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic
Daniel F. Jarosz: Stanford University School of Medicine
S. Stephen Yi: The University of Texas at Austin
M. Madan Babu: 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
Richard W. Kriwacki: St. Jude Children’s Research Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-25

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41655-2

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