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

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. Rouaen, Daniel R. Carter, Helen Forgham, Eric O. Sekyere, Joanna Keating, Georgina Eden, Sophie Allan, Stephanie Alfred, Frances K. Kusuma, Ashleigh Clark, Hannah Webber, Amanda J. Russell, Antoine Weck, Benjamin T. Kile, Martina Santulli, Piergiuseppe Rosa, Emmy D. G. Fleuren, Weiman Gao, Lorna Wilkinson-White, Jason K. K. Low, Joel P. Mackay, Glenn M. Marshall, Douglas J. Hilton, Federico M. Giorgi, Jan Koster, Giovanni Perini, Michelle Haber and Murray D. Norris ()
Additional contact information
Jayne E. Murray: UNSW Sydney
Emanuele Valli: UNSW Sydney
Giorgio Milazzo: University of Bologna
Chelsea Mayoh: UNSW Sydney
Andrew J. Gifford: UNSW Sydney
Jamie I. Fletcher: 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
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
Antoine Weck: UNSW Sydney
Benjamin T. Kile: Monash University
Martina Santulli: University of Bologna
Piergiuseppe Rosa: University of Bologna
Emmy D. G. Fleuren: 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
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
Murray D. Norris: UNSW Sydney

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49871-0

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