biostudies-literatureMurray JEAssociazione Italiana per la Ricerca sul CancroCancer Council NSWProfield Foundation Australia Tour de Cure Australia Neuroblastoma AustraliaUniversità di Bologna (University of Bologna)Università di BolognaDepartment of Health | National Health and Medical Research Council (NHMRC)Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research)Department of Health | National Health and Medical Research Council5585https://www.ebi.ac.uk/biostudies/studies/S-EPMC11239676biostudies-literatureUnknown15(1)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 PNature communicationsThe transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis.PMC11239676IG15182APP1132608IG24341RFOAPP1016699APP1083938Salehzadeh FAllan SXue CFleuren EDGMurray JEMackay JPFletcher JIGifford AJClark ANorris MDMilazzo GWilkinson-White LGiorgi FMKusuma FKCarter DRForgham HHaber MPerini GRussell AJKile BTLow JKKSekyere EOEden GValli EMayoh CRouaen JRCHilton DJKoster JWebber HSantulli MDe Rosa PKeating JMarshall GMAlfred Sde Weck AGao WJayatilleke NGamble LDfalseThe transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis.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 P2024-01-01T00:00:00Z2024 Jul2026-07-15T05:14:15.438Z2025-04-05T15:48:05.276ZS-EPMC112396763899204010.1038/s41467-024-49871-0