TitleAICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis.
Publication TypeJournal Article
Year of Publication2018
AuthorsTeater, Matt, Dominguez Pilar M., Redmond David, Chen Zhengming, Ennishi Daisuke, Scott David W., Cimmino Luisa, Ghione Paola, Chaudhuri Jayanta, Gascoyne Randy D., Aifantis Iannis, Inghirami Giorgio, Elemento Olivier, Melnick Ari, and Shaknovich Rita
JournalNat Commun
Volume9
Issue1
Pagination222
Date Published2018 01 15
ISSN2041-1723
KeywordsAnimals, B-Lymphocytes, Cytidine Deaminase, Epigenesis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Germinal Center, Humans, Lymphoma, Large B-Cell, Diffuse, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mutation
Abstract

<p>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.</p>

DOI10.1038/s41467-017-02595-w
Alternate JournalNat Commun
PubMed ID29335468
PubMed Central IDPMC5768781
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R01 CA194547 / CA / NCI NIH HHS / United States