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ResearchIn-Press PreviewGeneticsOncology Open Access | 10.1172/JCI190855

DNA demethylating agents suppress preclinical models of synovial sarcoma

Nobuhiko Hasegawa,1 Nezha S. Benabdallah,2 Kyllie Smith-Fry,1 Li Li,1 Sarah McCollum,1 Jinxiu Li,1 Caelen A. Jones,1 Lena Wagner,2 Vineet Dalal,2 Viola Golde,2 Anastasija Pejkovska,2 Lara Carroll,1 Malay Haldar,3 Seth M. Pollack,4 Scott W. Lowe,5 Torsten O. Nielsen,6 Ana Banito,2 and Kevin B. Jones1

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Hasegawa, N. in: PubMed | Google Scholar

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Benabdallah, N. in: PubMed | Google Scholar

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Smith-Fry, K. in: PubMed | Google Scholar

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Li, L. in: PubMed | Google Scholar

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by McCollum, S. in: PubMed | Google Scholar

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Li, J. in: PubMed | Google Scholar

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Jones, C. in: PubMed | Google Scholar

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Wagner, L. in: PubMed | Google Scholar

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Dalal, V. in: PubMed | Google Scholar

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Golde, V. in: PubMed | Google Scholar |

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Pejkovska, A. in: PubMed | Google Scholar

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Carroll, L. in: PubMed | Google Scholar |

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Haldar, M. in: PubMed | Google Scholar

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Pollack, S. in: PubMed | Google Scholar |

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Lowe, S. in: PubMed | Google Scholar |

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Nielsen, T. in: PubMed | Google Scholar

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Banito, A. in: PubMed | Google Scholar

1Department of Orthopaedics, University of Utah, Salt Lake City, United States of America

2Hopp Children's Cancer Center, Heidelberg, Germany

3Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States of America

4Department of Medicine, Feinberg School of Medicine at Northwestern University, Chicago, United States of America

5Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Institute, New York, United States of America

6Department of Pathology and Laboratory Medicine, Vancouver Coastal Health Research Institute and Faculty of Medicine, University of British Columbia, Vancouver, Canada

Find articles by Jones, K. in: PubMed | Google Scholar |

Published April 29, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI190855.
Copyright © 2025, Hasegawa et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published April 29, 2025 - Version history
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Abstract

Synovial sarcoma is an aggressive soft tissue cancer driven by the chimeric SS18::SSX fusion oncoprotein, which disrupts chromatin remodeling by combining two antagonistic transcriptional regulators. SS18 participates in BAF complexes that open chromatin, while the SSX genes are cancer-testis antigens that interface with chromatin decorated with monoubiquitinated histone H2A placed by Polycomb repressive complexes (PRCs) activity. Because KDM2B brings PRC to unmethylated CpG islands, it is plausible that methylation directly determines the distribution of SS18::SSX to target loci. Given that synovial sarcoma is also characterized by a peculiarly low DNA hypomethylation profile, we hypothesized that further disturbance of DNA methylation would have a negative impact on synovial sarcoma growth. DNMT1 disruption by CRISPR/Cas9 targeting or pharmacologic inhibition with cytidine analogs 5-aza-2ʹ-deoxycytidine (decitabine) and 5-azacytidine led to decreased genome-wide methylation, redistribution of SS18::SSX, and altered gene expression profiles, most prominently including upregulation of tumor suppressor genes, immune-related genes, and mesenchymal differentiation-related genes. These drugs suppressed growth of synovial sarcoma cell lines and drove cytoreduction in mouse genetic models. DNMT1 inhibitors, already approved for treating myelodysplastic syndromes, warrant further clinical investigation for synovial sarcoma as repurposed, targeted treatments exploiting a vulnerability in the intrinsic biology of this cancer.

Graphical Abstract
graphical abstract
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