AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis.

TitleAICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis.
Publication TypeJournal Article
Year of Publication2018
AuthorsTeater M, Dominguez PM, Redmond D, Chen Z, Ennishi D, Scott DW, Cimmino L, Ghione P, Chaudhuri J, Gascoyne RD, Aifantis I, Inghirami G, Elemento O, Melnick A, Shaknovich R
JournalNat Commun
Date Published2018 01 15
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

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.

Alternate JournalNat Commun
PubMed ID29335468
PubMed Central IDPMC5768781
Grant ListR01 CA194547 / CA / NCI NIH HHS / United States