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

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

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Publisher:: NATURE PORTFOLIO
Publication Type:: Journal Article
Citation:: Nat Commun, 2024, 15, (1), pp. 5585
Issue Date:: 2024-07-11

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Field	Value	Language
dc.contributor.author	Murray, JE
dc.contributor.author	Valli, E
dc.contributor.author	Milazzo, G
dc.contributor.author	Mayoh, C
dc.contributor.author	Gifford, AJ
dc.contributor.author	Fletcher, JI
dc.contributor.author	Xue, C
dc.contributor.author	Jayatilleke, N
dc.contributor.author	Salehzadeh, F
dc.contributor.author	Gamble, LD
dc.contributor.author	Rouaen, JRC
dc.contributor.author	Carter, DR
dc.contributor.author	Forgham, H
dc.contributor.author	Sekyere, EO
dc.contributor.author	Keating, J
dc.contributor.author	Eden, G
dc.contributor.author	Allan, S
dc.contributor.author	Alfred, S
dc.contributor.author	Kusuma, FK
dc.contributor.author	Clark, A
dc.contributor.author	Webber, H
dc.contributor.author	Russell, AJ
dc.contributor.author	de Weck, A
dc.contributor.author	Kile, BT
dc.contributor.author	Santulli, M
dc.contributor.author	De Rosa, P
dc.contributor.author	Fleuren, EDG
dc.contributor.author	Gao, W
dc.contributor.author	Wilkinson-White, L
dc.contributor.author	Low, JKK
dc.contributor.author	Mackay, JP
dc.contributor.author	Marshall, GM
dc.contributor.author	Hilton, DJ
dc.contributor.author	Giorgi, FM
dc.contributor.author	Koster, J
dc.contributor.author	Perini, G
dc.contributor.author	Haber, M
dc.contributor.author	Norris, MD
dc.date.accessioned	2024-08-01T04:47:41Z
dc.date.available	2024-06-23
dc.date.available	2024-08-01T04:47:41Z
dc.date.issued	2024-07-11
dc.identifier.citation	Nat Commun, 2024, 15, (1), pp. 5585
dc.identifier.issn	2041-1723
dc.identifier.issn	2041-1723
dc.identifier.uri	http://hdl.handle.net/10453/179967
dc.description.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.
dc.format	Electronic
dc.language	eng
dc.publisher	NATURE PORTFOLIO
dc.relation.ispartof	Nat Commun
dc.relation.isbasedon	10.1038/s41467-024-49871-0
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Animals
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Transcription Factors
dc.subject.mesh	Histone Demethylases
dc.subject.mesh	Co-Repressor Proteins
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Transcription Factors
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Histone Demethylases
dc.subject.mesh	Co-Repressor Proteins
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Animals
dc.subject.mesh	N-Myc Proto-Oncogene Protein
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Carcinogenesis
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Mice, Transgenic
dc.subject.mesh	Mice, Knockout
dc.subject.mesh	Transcription Factors
dc.subject.mesh	Histone Demethylases
dc.subject.mesh	Co-Repressor Proteins
dc.title	The transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis.
dc.type	Journal Article
utslib.citation.volume	15
utslib.location.activity	England
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	University of Technology Sydney/All Manual Groups
pubs.organisational-group	University of Technology Sydney/All Manual Groups/Centre for Health Technologies (CHT)
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
dc.date.updated	2024-08-01T04:47:32Z
pubs.issue	1
pubs.publication-status	Published online
pubs.volume	15
utslib.citation.issue	1

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.

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http://hdl.handle.net/10453/179967