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Abstract
Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.
The relationship between cellular histogenesis and molecular phenotypes for the EWSR1- ATF1 fusion in clear cell sarcoma (CCS) requires further characterization. Here, the authors investigate the EWSR1-ATF1 gene regulation networks in CCS cell lines, primary tumors, and mesenchymal stem cells.
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1 Lausanne University Hospital and University of Lausanne, Experimental Pathology Service, Lausanne, Switzerland (GRID:grid.8515.9) (ISNI:0000 0001 0423 4662)
2 Massachusetts General Hospital, Department of Pathology and Cancer Center, Charlestown, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924)
3 Lausanne University Hospital and University of Lausanne, Experimental Pathology Service, Lausanne, Switzerland (GRID:grid.8515.9) (ISNI:0000 0001 0423 4662); Massachusetts General Hospital, Department of Pathology and Cancer Center, Charlestown, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924)
4 Central Institute, Valais Hospital, Department of Histopathology, Sion, Switzerland (GRID:grid.418149.1) (ISNI:0000 0000 8631 6364); Lausanne University Hospital and University of Lausanne, Institute of Pathology, Lausanne, Switzerland (GRID:grid.8515.9) (ISNI:0000 0001 0423 4662)
5 ASST Sette Laghi, Department of Pathology, Varese, Italy (GRID:grid.8515.9)
6 Lausanne University Hospital and University of Lausanne, Institute of Pathology, Lausanne, Switzerland (GRID:grid.8515.9) (ISNI:0000 0001 0423 4662); University of Insubria, Pathology Unit, Department of Medicine and Surgery, Varese, Italy (GRID:grid.18147.3b) (ISNI:0000000121724807)
7 University of Insubria, Pathology Unit, Department of Medicine and Surgery, Varese, Italy (GRID:grid.18147.3b) (ISNI:0000000121724807)
8 Massachusetts General Hospital and Harvard Medical School, Department of Pathology, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924)
9 Lausanne University Hospital and University of Lausanne, Department of Oncology, Lausanne, Switzerland (GRID:grid.8515.9) (ISNI:0000 0001 0423 4662)
10 Massachusetts General Hospital, Department of Orthopaedic Surgery, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924)
11 Division of Hematology and Oncology, Massachusetts General Hospital, Department of Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924)
12 Massachusetts General Hospital, Department of Pathology and Cancer Center, Charlestown, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Broad Institute, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623)