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Super-enhancer hypermutation alters oncogene expression in B cell lymphoma

Author

Listed:
  • Elodie Bal

    (Columbia University)

  • Rahul Kumar

    (Columbia University
    Indian Institute of Technology Hyderabad)

  • Mohammad Hadigol

    (Rutgers University)

  • Antony B. Holmes

    (Columbia University)

  • Laura K. Hilton

    (BC Cancer Research Centre)

  • Jui Wan Loh

    (Rutgers University)

  • Kostiantyn Dreval

    (Simon Fraser University)

  • Jasper C. H. Wong

    (BC Cancer Research Centre)

  • Sofija Vlasevska

    (Columbia University)

  • Clarissa Corinaldesi

    (Columbia University)

  • Rajesh Kumar Soni

    (Columbia University
    Columbia University)

  • Katia Basso

    (Columbia University
    Columbia University)

  • Ryan D. Morin

    (Simon Fraser University
    BC Cancer Research Institute)

  • Hossein Khiabanian

    (Rutgers University
    Rutgers University)

  • Laura Pasqualucci

    (Columbia University
    Columbia University
    Columbia University)

  • Riccardo Dalla-Favera

    (Columbia University
    Columbia University
    Columbia University
    Columbia University)

Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common B cell non-Hodgkin lymphoma and remains incurable in around 40% of patients. Efforts to sequence the coding genome identified several genes and pathways that are altered in this disease, including potential therapeutic targets1–5. However, the non-coding genome of DLBCL remains largely unexplored. Here we show that active super-enhancers are highly and specifically hypermutated in 92% of samples from individuals with DLBCL, display signatures of activation-induced cytidine deaminase activity, and are linked to genes that encode B cell developmental regulators and oncogenes. As evidence of oncogenic relevance, we show that the hypermutated super-enhancers linked to the BCL6, BCL2 and CXCR4 proto-oncogenes prevent the binding and transcriptional downregulation of the corresponding target gene by transcriptional repressors, including BLIMP1 (targeting BCL6) and the steroid receptor NR3C1 (targeting BCL2 and CXCR4). Genetic correction of selected mutations restored repressor DNA binding, downregulated target gene expression and led to the counter-selection of cells containing corrected alleles, indicating an oncogenic dependency on the super-enhancer mutations. This pervasive super-enhancer mutational mechanism reveals a major set of genetic lesions deregulating gene expression, which expands the involvement of known oncogenes in DLBCL pathogenesis and identifies new deregulated gene targets of therapeutic relevance.

Suggested Citation

  • Elodie Bal & Rahul Kumar & Mohammad Hadigol & Antony B. Holmes & Laura K. Hilton & Jui Wan Loh & Kostiantyn Dreval & Jasper C. H. Wong & Sofija Vlasevska & Clarissa Corinaldesi & Rajesh Kumar Soni & K, 2022. "Super-enhancer hypermutation alters oncogene expression in B cell lymphoma," Nature, Nature, vol. 607(7920), pages 808-815, July.
  • Handle: RePEc:nat:nature:v:607:y:2022:i:7920:d:10.1038_s41586-022-04906-8
    DOI: 10.1038/s41586-022-04906-8
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    Citations

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    Cited by:

    1. Chuanjiang Yu & Qiong Shen & Antony B. Holmes & Tongwei Mo & Anna Tosato & Rajesh Kumar Soni & Clarissa Corinaldesi & Sanjay Koul & Laura Pasqualucci & Shafinaz Hussein & Farhad Forouhar & Riccardo Da, 2024. "MEF2B C-terminal mutations enhance transcriptional activity and stability to drive B cell lymphomagenesis," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Sebastian Carrasco Pro & Heather Hook & David Bray & Daniel Berenzy & Devlin Moyer & Meimei Yin & Adam Thomas Labadorf & Ryan Tewhey & Trevor Siggers & Juan Ignacio Fuxman Bass, 2023. "Widespread perturbation of ETS factor binding sites in cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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