Title | AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Authors | Teater, 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 |
Journal | Nat Commun |
Volume | 9 |
Issue | 1 |
Pagination | 222 |
Date Published | 2018 Jan 15 |
ISSN | 2041-1723 |
Keywords | Animals, 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> |
DOI | 10.1038/s41467-017-02595-w |
Alternate Journal | Nat Commun |
PubMed ID | 29335468 |
PubMed Central ID | PMC5768781 |
Grant List | P30 CA008748 / CA / NCI NIH HHS / United States R01 CA194547 / CA / NCI NIH HHS / United States |