Aberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma.
Daniel Aron AngJean-Michel CarterKamalakshi DekaJoel H L TanJianbiao ZhouQingfeng ChenWee Joo ChngNathan HarmstonYinghui LiPublished in: Nature communications (2024)
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.
Keyphrases
- multiple myeloma
- signaling pathway
- lps induced
- pi k akt
- transcription factor
- nuclear factor
- oxidative stress
- induced apoptosis
- bone marrow
- single cell
- inflammatory response
- cell cycle arrest
- gene expression
- public health
- dna methylation
- toll like receptor
- stem cells
- immune response
- newly diagnosed
- cell proliferation
- copy number