Aberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma

Ang, Daniel A., Carter, Jean-Michel, Deka, Kamalakshi, Tan, Joel H. L., Zhou, Jianbiao, Chen, Qingfeng, Chng, Wee Joo, Harmston, Nathan and Li, Yinghui 2024. Aberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma. Nature Communications 15 (1) , 2513. 10.1038/s41467-024-46728-4

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Abstract

In multiple myeloma, abnormal plasma cells establish oncogenic niches within the bone marrow by engaging the NF-κB pathway to nurture their survival while they accumulate pro-proliferative mutations. Under these conditions, many cases eventually develop genetic abnormalities endowing them with constitutive NF-κB activation. Here, we find that sustained NF-κB/p52 levels resulting from such mutations favours the recruitment of enhancers beyond the normal B-cell repertoire. Furthermore, through targeted disruption of p52, we characterise how such enhancers are complicit in the formation of super-enhancers and the establishment of cis-regulatory interactions with myeloma dependencies during constitutive activation of p52. Finally, we functionally validate the pathological impact of these cis-regulatory modules on cell and tumour phenotypes using in vitro and in vivo models, confirming RGS1 as a p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-κB signalling potentiates transcriptional programs beneficial for multiple myeloma progression.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Biosciences
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	22 March 2024
Date of Acceptance:	7 March 2024
Last Modified:	22 Mar 2024 10:00
URI:	https://orca.cardiff.ac.uk/id/eprint/167470

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