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

Murray, JE; Valli, E; Milazzo, G; Mayoh, C; Gifford, AJ; Fletcher, JI; Xue, C; Jayatilleke, N; Salehzadeh, F; Gamble, LD; Rouaen, JRC; Carter, DR; Forgham, H; Sekyere, EO; Keating, J; Eden, G; Allan, S; Alfred, S; Kusuma, FK; Clark, A; Webber, H; Russell, AJ; de Weck, A; Kile, BT; Santulli, M; De Rosa, P; Fleuren, EDG; Gao, W; Wilkinson-White, L; Low, JKK; Mackay, JP; Marshall, GM; Hilton, DJ; Giorgi, FM; Koster, J; Perini, G; Haber, M; Norris, MD

Author(s): Murray, JE; Valli, E; Milazzo, G; Mayoh, C; Gifford, AJ; Fletcher, JI; Xue, C; Jayatilleke, N; Salehzadeh, F; Gamble, LD; Rouaen, JRC; Carter, DR; Forgham, H; Sekyere, EO; Keating, J; Eden, G; Allan, S; Alfred, S; Kusuma, FK; Clark, A; Webber, H; Russell, AJ; de Weck, A; Kile, BT; Santulli, M; De Rosa, P; Fleuren, EDG; Gao, W; Wilkinson-White, L; Low, JKK; Mackay, JP; Marshall, GM; Hilton, DJ; Giorgi, FM; Koster, J; Perini, G; Haber, M; Norris, MD;
Details: Publication Year 2024-07-11,Volume 15,Issue #1,Page 5585
Journal Title: Nature Communications
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.
Publisher: Springer Nature
Keywords: Animals; Humans; Mice; *Carcinogenesis/genetics; Cell Line, Tumor; Co-Repressor Proteins/metabolism/genetics; Gene Expression Regulation, Neoplastic; Histone Demethylases/metabolism/genetics; Mice, Knockout; Mice, Transgenic; *N-Myc Proto-Oncogene Protein/genetics/metabolism; *Neuroblastoma/genetics/metabolism/pathology; Transcription Factors/metabolism/genetics
Research Division(s): Epigenetics And Development
PubMed ID: 38992040
Publisher's Version: https://doi.org/10.1038/s41467-024-49871-0
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-024-49871-0
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-01-20 02:14:00

Last Modified: 2025-01-21 10:48:42