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

Author

Listed:
  • 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
    National University of Singapore
    Centre for Translational Medicine)

  • Qingfeng Chen

    (Proteos)

  • Wee Joo Chng

    (Centre for Translational Medicine
    National University of Singapore
    Centre for Translational Medicine
    The National University Health System (NUHS))

  • Nathan Harmston

    (Yale-NUS College
    Duke-NUS Medical School
    Cardiff University)

  • Yinghui Li

    (Nanyang Technological University (NTU)
    Proteos)

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.

Suggested Citation

  • Daniel A. Ang & Jean-Michel Carter & Kamalakshi Deka & Joel H. L. Tan & Jianbiao Zhou & Qingfeng Chen & Wee Joo Chng & Nathan Harmston & Yinghui Li, 2024. "Aberrant non-canonical NF-κB signalling reprograms the epigenome landscape to drive oncogenic transcriptomes in multiple myeloma," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46728-4
    DOI: 10.1038/s41467-024-46728-4
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    References listed on IDEAS

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    1. Jaime Alvarez-Benayas & Nikolaos Trasanidis & Alexia Katsarou & Kanagaraju Ponnusamy & Aristeidis Chaidos & Philippa C. May & Xiaolin Xiao & Marco Bua & Maria Atta & Irene A. G. Roberts & Holger W. Au, 2021. "Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. Subrahmanya D. Vallabhapurapu & Sunil K. Noothi & Derek A. Pullum & Charles H. Lawrie & Rachel Pallapati & Veena Potluri & Christian Kuntzen & Sohaib Khan & David R. Plas & Robert Z. Orlowski & Marta , 2015. "Transcriptional repression by the HDAC4–RelB–p52 complex regulates multiple myeloma survival and growth," Nature Communications, Nature, vol. 6(1), pages 1-15, December.
    3. Xueyong Xu & Yinghui Li & Sakshibeedu R. Bharath & Mert Burak Ozturk & Matthew W. Bowler & Bryan Zong Lin Loo & Vinay Tergaonkar & Haiwei Song, 2018. "Structural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
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