1. The transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis
- Author
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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, and Murray D. Norris
- Subjects
Science - 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.
- Published
- 2024
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