AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis

Matt Teater,Olivier Elemento,Rita Shaknovich,Jayanta Chaudhuri,Giorgio Inghirami,Paola Ghione,David Redmond,Daisuke Ennishi,Pilar M Dominguez,Ari Melnick,Zhengming Chen,Iannis Aifantis,Randy D Gascoyne,Luisa Cimmino,David W Scott

doi:10.1038/s41467-017-02595-w

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.

Highlights

Epigenetic heterogeneity is emerging as a feature of tumors
We find that Activation-induced cytidine deaminase (AICDA) expression may be among the contributing factors to both the inferior outcome and greater epigenetic heterogeneity observed in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL)
Besides the role of AICDA in modifying cytosine methylation during the germinal center (GC) reaction[13], the data showed in the present manuscript suggests that AICDA is a critical source of epigenetic heterogeneity in DLBCL

Summary

Introduction

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. 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. 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 Bcell lymphomas with potential significance for other tumors with aberrant expression of cytidine deaminases. We find that AICDA expression may be among the contributing factors to both the inferior outcome and greater epigenetic heterogeneity observed in the activated B-cell-like (ABC) subtype of DLBCL

Methods

Results

Conclusion