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@ARTICLE{Hasegawa:301550,
      author       = {N. Hasegawa and N. S. Benabdallah$^*$ and K. Smith-Fry and
                      L. Li and S. McCollum and J. Li and C. A. Jones and L.
                      Wagner$^*$ and V. Dalal$^*$ and V. Golde$^*$ and A.
                      Pejkovska$^*$ and L. Carroll and M. Haldar and S. M. Pollack
                      and S. W. Lowe and T. O. Nielsen and A. Banito$^*$ and K. B.
                      Jones},
      title        = {{DNA} demethylating agents suppress preclinical models of
                      synovial sarcoma.},
      journal      = {The journal of clinical investigation},
      volume       = {135},
      number       = {13},
      issn         = {0021-9738},
      address      = {Ann Arbor, Mich.},
      publisher    = {ASCJ},
      reportid     = {DKFZ-2025-01071},
      pages        = {e190855},
      year         = {2025},
      note         = {#EA:B380#LA:B380# / 2025 Apr 29;135(13):e190855},
      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-2'-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.},
      keywords     = {Cancer (Other) / Epigenetics (Other) / Expression profiling
                      (Other) / Genetics (Other) / Oncology (Other)},
      cin          = {B380},
      ddc          = {610},
      cid          = {I:(DE-He78)B380-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40299558},
      doi          = {10.1172/JCI190855},
      url          = {https://inrepo02.dkfz.de/record/301550},
}