Aberrant non-canonical NF-?B signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma [ATAC-seq]

In multiple myeloma, abnormal plasma cells establish oncogenic niches within the bone marrow by engaging the NF-?B 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-?B activation. Here, we find that sustained NF-?B/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 novel p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-?B signalling potentiates transcriptional programs beneficial for multiple myeloma progression. Overall design: Assay for transposase-accessible chromatin with DNA-sequencing (ATAC-seq) in multiple myeloma cell lines KMS-11 and MM1.144 subjected to p52 knock down.