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

Overview

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

  • January 15, 2018

Research

keywords

  • Cytidine Deaminase
  • Epigenesis, Genetic
  • Germinal Center
  • Lymphoma, Large B-Cell, Diffuse

Identity

PubMed Central ID

  • PMC5768781

Scopus Document Identifier

  • 85040792130

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2008.03.028

PubMed ID

  • 29335468

Additional Document Info

volume

  • 9

issue

  • 1