AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis Academic Article uri icon

Overview

MeSH Major

  • Enzyme Inhibitors
  • Nitric Oxide Synthase Type II
  • Ribosomal Proteins
  • Triple Negative Breast Neoplasms
  • omega-N-Methylarginine

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.

publication date

  • December 2018

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5768781

Digital Object Identifier (DOI)

  • 10.1038/s41467-017-02595-w

PubMed ID

  • 29335468

Additional Document Info

start page

  • 222

volume

  • 9

number

  • 1