AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis

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 Inghirami, Olivier Elemento, Ari Melnick, Rita Shaknovich

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Article number222
JournalNature communications
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Fingerprint Dive into the research topics of 'AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis'. Together they form a unique fingerprint.

  • Cite this

    Teater, M., Dominguez, P. M., Redmond, D., Chen, Z., Ennishi, D., Scott, D. W., Cimmino, L., Ghione, P., Chaudhuri, J., Gascoyne, R. D., Aifantis, I., Inghirami, G., Elemento, O., Melnick, A., & Shaknovich, R. (2018). AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis. Nature communications, 9(1), [222]. https://doi.org/10.1038/s41467-017-02595-w