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EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in desmoplastic small round cell tumors.
Boulay, Gaylor; Broye, Liliane C; Dong, Rui; Iyer, Sowmya; Sanalkumar, Rajendran; Xing, Yu-Hang; Buisson, Rémi; Rengarajan, Shruthi; Naigles, Beverly; Duc, Benoît; Volorio, Angela; Awad, Mary E; Renella, Raffaele; Chebib, Ivan; Nielsen, G Petur; Choy, Edwin; Cote, Gregory M; Zou, Lee; Letovanec, Igor; Stamenkovic, Ivan; Rivera, Miguel N; Riggi, Nicolò.
Afiliación
  • Boulay G; Department of Pathology & Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Broye LC; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Dong R; Experimental Pathology Service, Lausanne University Hospital & University of Lausanne, Lausanne, Switzerland.
  • Iyer S; Department of Pathology & Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Sanalkumar R; Department of Pathology & Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Xing YH; Experimental Pathology Service, Lausanne University Hospital & University of Lausanne, Lausanne, Switzerland.
  • Buisson R; Department of Pathology & Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Rengarajan S; Department of Pathology & Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Naigles B; Department of Pathology & Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Duc B; Department of Pathology & Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Volorio A; Experimental Pathology Service, Lausanne University Hospital & University of Lausanne, Lausanne, Switzerland.
  • Awad ME; Department of Pathology & Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Renella R; Department of Pathology & Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Chebib I; Department Woman-Mother-Child, Division of Pediatrics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
  • Nielsen GP; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Choy E; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Cote GM; Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA.
  • Zou L; Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA.
  • Letovanec I; Department of Pathology & Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Stamenkovic I; Department of Histopathology, Central Institute, Valais Hospital, Sion, Switzerland.
  • Rivera MN; Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
  • Riggi N; Experimental Pathology Service, Lausanne University Hospital & University of Lausanne, Lausanne, Switzerland.
Nat Commun ; 15(1): 7460, 2024 Aug 28.
Article en En | MEDLINE | ID: mdl-39198430
ABSTRACT
EWS fusion oncoproteins underlie several human malignancies including Desmoplastic Small Round Cell Tumor (DSRCT), an aggressive cancer driven by EWS-WT1 fusion proteins. Here we combine chromatin occupancy and 3D profiles to identify EWS-WT1-dependent gene regulation networks and target genes. We show that EWS-WT1 is a powerful chromatin activator controlling an oncogenic gene expression program that characterizes primary tumors. Similar to wild type WT1, EWS-WT1 has two isoforms that differ in their DNA binding domain and we find that they have distinct DNA binding profiles and are both required to generate viable tumors that resemble primary DSRCT. Finally, we identify candidate EWS-WT1 target genes with potential therapeutic implications, including CCND1, whose inhibition by the clinically-approved drug Palbociclib leads to marked tumor burden decrease in DSRCT PDXs in vivo. Taken together, our studies identify gene regulation programs and therapeutic vulnerabilities in DSRCT and provide a mechanistic understanding of the complex oncogenic activity of EWS-WT1.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Regulación Neoplásica de la Expresión Génica / Proteínas de Fusión Oncogénica / Ciclina D1 / Isoformas de Proteínas / Proteína EWS de Unión a ARN / Tumor Desmoplásico de Células Pequeñas Redondas Límite: Animals / Female / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Regulación Neoplásica de la Expresión Génica / Proteínas de Fusión Oncogénica / Ciclina D1 / Isoformas de Proteínas / Proteína EWS de Unión a ARN / Tumor Desmoplásico de Células Pequeñas Redondas Límite: Animals / Female / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido