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

Autor: Ang DA; School of Biological Sciences (SBS), Nanyang Technological University (NTU), 60 Nanyang Drive, Singapore, 637551, Singapore., Carter JM; School of Biological Sciences (SBS), Nanyang Technological University (NTU), 60 Nanyang Drive, Singapore, 637551, Singapore., Deka K; School of Biological Sciences (SBS), Nanyang Technological University (NTU), 60 Nanyang Drive, Singapore, 637551, Singapore., Tan JHL; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore., Zhou J; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Republic of Singapore.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Republic of Singapore.; NUS Centre for Cancer Research, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Singapore., Chen Q; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore., Chng WJ; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Republic of Singapore.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Republic of Singapore.; NUS Centre for Cancer Research, 14 Medical Drive, Centre for Translational Medicine, Singapore, 117599, Singapore.; Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), The National University Health System (NUHS), 1E, Kent Ridge Road, Singapore, 119228, Republic of Singapore., Harmston N; Division of Science, Yale-NUS College, Singapore, 138527, Singapore.; Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, 169857, Singapore.; Molecular Biosciences Division, Cardiff School of Biosciences, Cardiff University, Cardiff, CF10 3AX, UK., Li Y; School of Biological Sciences (SBS), Nanyang Technological University (NTU), 60 Nanyang Drive, Singapore, 637551, Singapore. liyh@ntu.edu.sg.; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore. liyh@ntu.edu.sg.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Mar 21; Vol. 15 (1), pp. 2513. Date of Electronic Publication: 2024 Mar 21.
DOI: 10.1038/s41467-024-46728-4
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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