Disruption of KMT2D Perturbs Germinal Center B Cell Development and Promotes Lymphomagenesis

Nat Med. 2015 Oct;21(10):1190-8. doi: 10.1038/nm.3940. Epub 2015 Sep 14.

Abstract

Mutations in the gene encoding the KMT2D (or MLL2) methyltransferase are highly recurrent and occur early during tumorigenesis in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). However, the functional consequences of these mutations and their role in lymphomagenesis are unknown. Here we show that FL- and DLBCL-associated KMT2D mutations impair KMT2D enzymatic activity, leading to diminished global H3K4 methylation in germinal-center (GC) B cells and DLBCL cells. Conditional deletion of Kmt2d early during B cell development, but not after initiation of the GC reaction, results in an increase in GC B cells and enhances B cell proliferation in mice. Moreover, genetic ablation of Kmt2d in mice overexpressing Bcl2 increases the incidence of GC-derived lymphomas resembling human tumors. These findings suggest that KMT2D acts as a tumor suppressor gene whose early loss facilitates lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of KMT2D-deficient cells may thus represent a rational therapeutic approach for targeting early tumorigenic events.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / pathology
  • Cell Proliferation
  • DNA Methylation
  • DNA-Binding Proteins / genetics*
  • Epigenesis, Genetic
  • Gene Silencing
  • Germinal Center / cytology*
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / etiology
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Mice
  • Mutation, Missense
  • Neoplasm Proteins / genetics*
  • Transcription, Genetic

Substances

  • DNA-Binding Proteins
  • KMT2D protein, human
  • Neoplasm Proteins

Associated data

  • GEO/GSE67388
  • GEO/GSE67494