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The transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis

Author

Listed:
  • Jayne E. Murray

    (UNSW Sydney
    UNSW Sydney)

  • Emanuele Valli

    (UNSW Sydney)

  • Giorgio Milazzo

    (University of Bologna)

  • Chelsea Mayoh

    (UNSW Sydney
    UNSW Sydney)

  • Andrew J. Gifford

    (UNSW Sydney
    UNSW Sydney
    Prince of Wales Hospital)

  • Jamie I. Fletcher

    (UNSW Sydney
    UNSW Sydney)

  • Chengyuan Xue

    (UNSW Sydney)

  • Nisitha Jayatilleke

    (UNSW Sydney)

  • Firoozeh Salehzadeh

    (UNSW Sydney)

  • Laura D. Gamble

    (UNSW Sydney)

  • Jourdin R. C. Rouaen

    (UNSW Sydney)

  • Daniel R. Carter

    (UNSW Sydney
    UNSW Sydney
    University of Technology Sydney)

  • Helen Forgham

    (UNSW Sydney)

  • Eric O. Sekyere

    (UNSW Sydney)

  • Joanna Keating

    (UNSW Sydney)

  • Georgina Eden

    (UNSW Sydney)

  • Sophie Allan

    (UNSW Sydney)

  • Stephanie Alfred

    (UNSW Sydney)

  • Frances K. Kusuma

    (UNSW Sydney)

  • Ashleigh Clark

    (UNSW Sydney)

  • Hannah Webber

    (UNSW Sydney)

  • Amanda J. Russell

    (UNSW Sydney
    Garvan Institute of Medical Research)

  • Antoine Weck

    (UNSW Sydney)

  • Benjamin T. Kile

    (Monash University
    The Walter and Eliza Hall Institute of Medical Research)

  • Martina Santulli

    (University of Bologna)

  • Piergiuseppe Rosa

    (University of Bologna)

  • Emmy D. G. Fleuren

    (UNSW Sydney
    UNSW Sydney)

  • Weiman Gao

    (UNSW Sydney)

  • Lorna Wilkinson-White

    (The University of Sydney)

  • Jason K. K. Low

    (The University of Sydney)

  • Joel P. Mackay

    (The University of Sydney)

  • Glenn M. Marshall

    (UNSW Sydney
    UNSW Sydney
    Sydney Children’s Hospital)

  • Douglas J. Hilton

    (The Walter and Eliza Hall Institute of Medical Research)

  • Federico M. Giorgi

    (University of Bologna)

  • Jan Koster

    (University of Amsterdam)

  • Giovanni Perini

    (University of Bologna)

  • Michelle Haber

    (UNSW Sydney
    UNSW Sydney)

  • Murray D. Norris

    (UNSW Sydney
    UNSW Sydney)

Abstract

MYCN oncogene amplification is frequently observed in aggressive childhood neuroblastoma. Using an unbiased large-scale mutagenesis screen in neuroblastoma-prone transgenic mice, we identify a single germline point mutation in the transcriptional corepressor Runx1t1, which abolishes MYCN-driven tumorigenesis. This loss-of-function mutation disrupts a highly conserved zinc finger domain within Runx1t1. Deletion of one Runx1t1 allele in an independent Runx1t1 knockout mouse model is also sufficient to prevent MYCN-driven neuroblastoma development, and reverse ganglia hyperplasia, a known pre-requisite for tumorigenesis. Silencing RUNX1T1 in human neuroblastoma cells decreases colony formation in vitro, and inhibits tumor growth in vivo. Moreover, RUNX1T1 knockdown inhibits the viability of PAX3-FOXO1 fusion-driven rhabdomyosarcoma and MYC-driven small cell lung cancer cells. Despite the role of Runx1t1 in MYCN-driven tumorigenesis neither gene directly regulates the other. We show RUNX1T1 forms part of a transcriptional LSD1-CoREST3-HDAC repressive complex recruited by HAND2 to enhancer regions to regulate chromatin accessibility and cell-fate pathway genes.

Suggested Citation

  • Jayne E. Murray & Emanuele Valli & Giorgio Milazzo & Chelsea Mayoh & Andrew J. Gifford & Jamie I. Fletcher & Chengyuan Xue & Nisitha Jayatilleke & Firoozeh Salehzadeh & Laura D. Gamble & Jourdin R. C., 2024. "The transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49871-0
    DOI: 10.1038/s41467-024-49871-0
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