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EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in desmoplastic small round cell tumors

Author

Listed:
  • Gaylor Boulay

    (Massachusetts General Hospital and Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Liliane C. Broye

    (Lausanne University Hospital & University of Lausanne)

  • Rui Dong

    (Massachusetts General Hospital and Harvard Medical School)

  • Sowmya Iyer

    (Massachusetts General Hospital and Harvard Medical School)

  • Rajendran Sanalkumar

    (Lausanne University Hospital & University of Lausanne)

  • Yu-Hang Xing

    (Massachusetts General Hospital and Harvard Medical School)

  • Rémi Buisson

    (Massachusetts General Hospital and Harvard Medical School)

  • Shruthi Rengarajan

    (Massachusetts General Hospital and Harvard Medical School)

  • Beverly Naigles

    (Massachusetts General Hospital and Harvard Medical School)

  • Benoît Duc

    (Lausanne University Hospital & University of Lausanne)

  • Angela Volorio

    (Massachusetts General Hospital and Harvard Medical School)

  • Mary E. Awad

    (Massachusetts General Hospital and Harvard Medical School)

  • Raffaele Renella

    (Lausanne University Hospital and University of Lausanne)

  • Ivan Chebib

    (Massachusetts General Hospital and Harvard Medical School)

  • G. Petur Nielsen

    (Massachusetts General Hospital and Harvard Medical School)

  • Edwin Choy

    (Massachusetts General Hospital)

  • Gregory M. Cote

    (Massachusetts General Hospital)

  • Lee Zou

    (Massachusetts General Hospital and Harvard Medical School)

  • Igor Letovanec

    (Valais Hospital
    Lausanne University Hospital and University of Lausanne)

  • Ivan Stamenkovic

    (Lausanne University Hospital & University of Lausanne)

  • Miguel N. Rivera

    (Massachusetts General Hospital and Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Nicolò Riggi

    (Lausanne University Hospital & University of Lausanne
    Department of Cell and Tissue Genomics (CTG))

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.

Suggested Citation

  • Gaylor Boulay & Liliane C. Broye & Rui Dong & Sowmya Iyer & Rajendran Sanalkumar & Yu-Hang Xing & Rémi Buisson & Shruthi Rengarajan & Beverly Naigles & Benoît Duc & Angela Volorio & Mary E. Awad & Raf, 2024. "EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in desmoplastic small round cell tumors," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51851-3
    DOI: 10.1038/s41467-024-51851-3
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    References listed on IDEAS

    as
    1. Michael Lawrence & Wolfgang Huber & Hervé Pagès & Patrick Aboyoun & Marc Carlson & Robert Gentleman & Martin T Morgan & Vincent J Carey, 2013. "Software for Computing and Annotating Genomic Ranges," PLOS Computational Biology, Public Library of Science, vol. 9(8), pages 1-10, August.
    2. Salah-Eddine Lamhamedi-Cherradi & Mayinuer Maitituoheti & Brian A. Menegaz & Sandhya Krishnan & Amelia M. Vetter & Pamela Camacho & Chia-Chin Wu & Hannah C. Beird & Robert W. Porter & Davis R. Ingram , 2022. "The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Tarjei S. Mikkelsen & Manching Ku & David B. Jaffe & Biju Issac & Erez Lieberman & Georgia Giannoukos & Pablo Alvarez & William Brockman & Tae-Kyung Kim & Richard P. Koche & William Lee & Eric Mendenh, 2007. "Genome-wide maps of chromatin state in pluripotent and lineage-committed cells," Nature, Nature, vol. 448(7153), pages 553-560, August.
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