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Under these conditions, many cases eventually develop genetic abnormalities endowing them with constitutive NF-\u03baB activation. Here, we find that sustained NF-\u03baB\/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\n                    <jats:italic>cis<\/jats:italic>\n                    -regulatory interactions with myeloma dependencies during constitutive activation of p52. Finally, we functionally validate the pathological impact of these\n                    <jats:italic>cis<\/jats:italic>\n                    -regulatory modules on cell and tumour phenotypes using in vitro and in vivo models, confirming\n                    <jats:italic>RGS1<\/jats:italic>\n                    as a p52-dependent myeloma driver. We conclude that the divergent epigenomic reprogramming enforced by aberrant non-canonical NF-\u03baB signalling potentiates transcriptional programs beneficial for multiple myeloma progression.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-46728-4","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T02:01:52Z","timestamp":1710986512000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Aberrant non-canonical NF-\u03baB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5868-5458","authenticated-orcid":false,"given":"Daniel A.","family":"Ang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7932-2368","authenticated-orcid":false,"given":"Jean-Michel","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamalakshi","family":"Deka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9152-7451","authenticated-orcid":false,"given":"Joel H. 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