AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis Journal Article

Authors: 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.
Article Title: AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis
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. © 2018 The Author(s).
Keywords: controlled study; human tissue; methylation; somatic mutation; mutation; nonhuman; genetic analysis; animal cell; mouse; phenotype; animal tissue; gene overexpression; protein bcl 2; gene expression; animal experiment; animal model; genetic transcription; enzyme activity; dna methylation; carcinogenesis; germinal center; activation induced cytidine deaminase; epigenetics; murinae; pathogenicity; tumor; genetic heterogeneity; cell; heterogeneity; cytosine; diffuse large b cell lymphoma; lymphomagenesis; human; article
Journal Title: Nature Communications
Volume: 9
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2018-01-15
Start Page: 222
Language: English
DOI: 10.1038/s41467-017-02595-w
PROVIDER: scopus
PMCID: PMC5768781
PUBMED: 29335468
Notes: Article -- Export Date: 1 February 2018 -- Source: Scopus
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