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; Richard W. Kriwacki

doi:10.1038/s41467-023-41655-2

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. McGrailDaniel F. Jarosz, S. Stephen Yi, M. Madan Babu, Charles G. Mullighan, Jinghui Zhang, Nidhi Sahni, Richard W. Kriwacki

Epigenetics & Molecular Carcinogenesis

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English (US)
Article number	6008
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-41655-2
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Tripathi, S., Shirnekhi, H. K., Gorman, S. D., Chandra, B., Baggett, D. W., Park, C. G., Somjee, R., Lang, B., Hosseini, S. M. H., Pioso, B. J., Li, Y., Iacobucci, I., Gao, Q., Edmonson, M. N., Rice, S. V., Zhou, X., Bollinger, J., Mitrea, D. M., White, M. R., ... Kriwacki, R. W. (2023). Defining the condensate landscape of fusion oncoproteins. Nature communications, 14(1), Article 6008. https://doi.org/10.1038/s41467-023-41655-2

Tripathi, S, Shirnekhi, HK, Gorman, SD, Chandra, B, Baggett, DW, Park, CG, Somjee, R, Lang, B, Hosseini, SMH, Pioso, BJ, Li, Y, Iacobucci, I, Gao, Q, Edmonson, MN, Rice, SV, Zhou, X, Bollinger, J, Mitrea, DM, White, MR, McGrail, DJ, Jarosz, DF, Yi, SS, Babu, MM, Mullighan, CG, Zhang, J, Sahni, N & Kriwacki, RW 2023, 'Defining the condensate landscape of fusion oncoproteins', Nature communications, vol. 14, no. 1, 6008. https://doi.org/10.1038/s41467-023-41655-2

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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.",

author = "Swarnendu Tripathi and Shirnekhi, {Hazheen K.} and Gorman, {Scott D.} and Bappaditya Chandra and Baggett, {David W.} and Park, {Cheon Gil} and Ramiz Somjee and Benjamin Lang and Hosseini, {Seyed Mohammad Hadi} and Pioso, {Brittany J.} and Yongsheng Li and Ilaria Iacobucci and Qingsong Gao and Edmonson, {Michael N.} and Rice, {Stephen V.} and Xin Zhou and John Bollinger and Mitrea, {Diana M.} and White, {Michael R.} and McGrail, {Daniel J.} and Jarosz, {Daniel F.} and Yi, {S. Stephen} and Babu, {M. Madan} and Mullighan, {Charles G.} and Jinghui Zhang and Nidhi Sahni and Kriwacki, {Richard W.}",

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doi = "10.1038/s41467-023-41655-2",

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AU - Tripathi, Swarnendu

AU - Shirnekhi, Hazheen K.

AU - Gorman, Scott D.

AU - Chandra, Bappaditya

AU - Baggett, David W.

AU - Park, Cheon Gil

AU - Somjee, Ramiz

AU - Lang, Benjamin

AU - Hosseini, Seyed Mohammad Hadi

AU - Pioso, Brittany J.

AU - Li, Yongsheng

AU - Iacobucci, Ilaria

AU - Gao, Qingsong

AU - Edmonson, Michael N.

AU - Rice, Stephen V.

AU - Zhou, Xin

AU - Bollinger, John

AU - Mitrea, Diana M.

AU - White, Michael R.

AU - McGrail, Daniel J.

AU - Jarosz, Daniel F.

AU - Yi, S. Stephen

AU - Babu, M. Madan

AU - Mullighan, Charles G.

AU - Zhang, Jinghui

AU - Sahni, Nidhi

AU - Kriwacki, Richard W.

PY - 2023/12

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N2 - 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.

AB - 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.

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Defining the condensate landscape of fusion oncoproteins

Abstract

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