Nature Communications (Jul 2024)
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 de Weck,
- Benjamin T. Kile,
- Martina Santulli,
- Piergiuseppe De 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,
- Murray D. Norris
Affiliations
- Jayne E. Murray
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Emanuele Valli
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Giorgio Milazzo
- Department of Pharmacy and Biotechnology, University of Bologna
- Chelsea Mayoh
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Andrew J. Gifford
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Jamie I. Fletcher
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Chengyuan Xue
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Nisitha Jayatilleke
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Firoozeh Salehzadeh
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Laura D. Gamble
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Jourdin R. C. Rouaen
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Daniel R. Carter
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Helen Forgham
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Eric O. Sekyere
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Joanna Keating
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Georgina Eden
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Sophie Allan
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Stephanie Alfred
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Frances K. Kusuma
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Ashleigh Clark
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Hannah Webber
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Amanda J. Russell
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Antoine de Weck
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Benjamin T. Kile
- Monash Biomedicine Discovery Institute, Monash University
- Martina Santulli
- Department of Pharmacy and Biotechnology, University of Bologna
- Piergiuseppe De Rosa
- Department of Pharmacy and Biotechnology, University of Bologna
- Emmy D. G. Fleuren
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Weiman Gao
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Lorna Wilkinson-White
- Sydney Analytical Core Research Facility, The University of Sydney
- Jason K. K. Low
- School of Life and Environmental Sciences, The University of Sydney
- Joel P. Mackay
- School of Life and Environmental Sciences, The University of Sydney
- Glenn M. Marshall
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Douglas J. Hilton
- The Walter and Eliza Hall Institute of Medical Research
- Federico M. Giorgi
- Department of Pharmacy and Biotechnology, University of Bologna
- Jan Koster
- Academic Medical Center, University of Amsterdam
- Giovanni Perini
- Department of Pharmacy and Biotechnology, University of Bologna
- Michelle Haber
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- Murray D. Norris
- Children’s Cancer Institute, Lowy Cancer Centre, UNSW Sydney
- DOI
- https://doi.org/10.1038/s41467-024-49871-0
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
