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

Daniel A. Ang, Jean-Michel Carter, Kamalakshi Deka, Joel H. L. Tan, Jianbiao Zhou, Qingfeng Chen, Wee Joo Chng, Nathan Harmston and Yinghui Li ()
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Daniel A. Ang: Nanyang Technological University (NTU)
Jean-Michel Carter: Nanyang Technological University (NTU)
Kamalakshi Deka: Nanyang Technological University (NTU)
Joel H. L. Tan: Proteos
Jianbiao Zhou: Centre for Translational Medicine
Qingfeng Chen: Proteos
Wee Joo Chng: Centre for Translational Medicine
Nathan Harmston: Yale-NUS College
Yinghui Li: Nanyang Technological University (NTU)

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46728-4

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