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

Autor:	Murray JE; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia.; School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia., Valli E; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Milazzo G; Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy., Mayoh C; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia.; School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia., Gifford AJ; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia.; School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia.; Anatomical Pathology, NSW Health Pathology, Prince of Wales Hospital, Randwick, NSW, Australia., Fletcher JI; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia.; School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia., Xue C; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Jayatilleke N; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Salehzadeh F; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Gamble LD; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Rouaen JRC; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Carter DR; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia.; School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia.; School of Biomedical Engineering, University of Technology Sydney, Broadway, NSW, Australia., Forgham H; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Sekyere EO; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Keating J; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Eden G; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Allan S; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Alfred S; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Kusuma FK; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Clark A; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Webber H; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Russell AJ; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia.; Garvan Institute of Medical Research, Darlinghurst, NSW, Australia., de Weck A; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Kile BT; Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia., Santulli M; Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy., De Rosa P; Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy., Fleuren EDG; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia.; School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia., Gao W; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia., Wilkinson-White L; Sydney Analytical Core Research Facility, The University of Sydney, Sydney, NSW, Australia., Low JKK; School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia., Mackay JP; School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia., Marshall GM; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia.; School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia.; Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia., Hilton DJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia., Giorgi FM; Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy., Koster J; Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands., Perini G; Department of Pharmacy and Biotechnology, University of Bologna, 40126, Bologna, Italy., Haber M; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia.; School of Clinical Medicine, UNSW Sydney, Sydney, NSW, Australia., Norris MD; Children's Cancer Institute, Lowy Cancer Centre, UNSW Sydney, Kensington, NSW, 2031, Australia. mnorris@ccia.unsw.edu.au.; UNSW Centre for Childhood Cancer Research, UNSW Sydney, Sydney, NSW, Australia. mnorris@ccia.unsw.edu.au.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2024 Jul 11; Vol. 15 (1), pp. 5585. Date of Electronic Publication: 2024 Jul 11.
DOI:	10.1038/s41467-024-49871-0
Abstrakt:	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. (© 2024. The Author(s).)
Databáze:	MEDLINE
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