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AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis

Author

Listed:
  • Matt Teater

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Pilar M. Dominguez

    (Weill Cornell Medicine)

  • David Redmond

    (Weill Cornell Medicine)

  • Zhengming Chen

    (Weill Cornell Medicine)

  • Daisuke Ennishi

    (British Columbia Cancer Agency)

  • David W. Scott

    (British Columbia Cancer Agency)

  • Luisa Cimmino

    (NYU School of Medicine)

  • Paola Ghione

    (Weill Cornell Medicine
    University of Turin)

  • Jayanta Chaudhuri

    (Gerstner Sloan-Kettering Graduate School)

  • Randy D. Gascoyne

    (British Columbia Cancer Agency)

  • Iannis Aifantis

    (NYU School of Medicine)

  • Giorgio Inghirami

    (Weill Cornell Medicine)

  • Olivier Elemento

    (Weill Cornell Medicine
    Weill Cornell Medicine)

  • Ari Melnick

    (Weill Cornell Medicine)

  • Rita Shaknovich

    (Weill Cornell Medicine
    Cancer Genetics, Inc.)

Abstract

Epigenetic heterogeneity is emerging as a feature of tumors. In diffuse large B-cell lymphoma (DLBCL), increased cytosine methylation heterogeneity is associated with poor clinical outcome, yet the underlying mechanisms remain unclear. Activation-induced cytidine deaminase (AICDA), an enzyme that mediates affinity maturation and facilitates DNA demethylation in germinal center (GC) B cells, is required for DLBCL pathogenesis and linked to inferior outcome. Here we show that AICDA overexpression causes more aggressive disease in BCL2-driven murine lymphomas. This phenotype is associated with increased cytosine methylation heterogeneity, but not with increased AICDA-mediated somatic mutation burden. Reciprocally, the cytosine methylation heterogeneity characteristic of normal GC B cells is lost upon AICDA depletion. These observations are relevant to human patients, since DLBCLs with high AICDA expression manifest increased methylation heterogeneity vs. AICDA-low DLBCLs. Our results identify AICDA as a driver of epigenetic heterogeneity in B-cell lymphomas with potential significance for other tumors with aberrant expression of cytidine deaminases.

Suggested Citation

  • Matt Teater & Pilar M. Dominguez & David Redmond & Zhengming Chen & Daisuke Ennishi & David W. Scott & Luisa Cimmino & Paola Ghione & Jayanta Chaudhuri & Randy D. Gascoyne & Iannis Aifantis & Giorgio , 2018. "AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-02595-w
    DOI: 10.1038/s41467-017-02595-w
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    Cited by:

    1. Clara Cousu & Eléonore Mulot & Annie Smet & Sara Formichetti & Damiana Lecoeuche & Jianke Ren & Kathrin Muegge & Matthieu Boulard & Jean-Claude Weill & Claude-Agnès Reynaud & Sébastien Storck, 2023. "Germinal center output is sustained by HELLS-dependent DNA-methylation-maintenance in B cells," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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