The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development Academic Article uri icon

Overview

MeSH Major

  • DNA-Binding Proteins
  • Gene Expression Regulation
  • Lymphoma, B-Cell
  • Neoplasm Proteins

abstract

  • The gene encoding the lysine-specific histone methyltransferase KMT2D has emerged as one of the most frequently mutated genes in follicular lymphoma and diffuse large B cell lymphoma; however, the biological consequences of KMT2D mutations on lymphoma development are not known. Here we show that KMT2D functions as a bona fide tumor suppressor and that its genetic ablation in B cells promotes lymphoma development in mice. KMT2D deficiency also delays germinal center involution and impedes B cell differentiation and class switch recombination. Integrative genomic analyses indicate that KMT2D affects methylation of lysine 4 on histone H3 (H3K4) and expression of a set of genes, including those in the CD40, JAK-STAT, Toll-like receptor and B cell receptor signaling pathways. Notably, other KMT2D target genes include frequently mutated tumor suppressor genes such as TNFAIP3, SOCS3 and TNFRSF14. Therefore, KMT2D mutations may promote malignant outgrowth by perturbing the expression of tumor suppressor genes that control B cell-activating pathways.

publication date

  • October 2015

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4676270

Digital Object Identifier (DOI)

  • 10.1038/nm.3943

PubMed ID

  • 26366710

Additional Document Info

start page

  • 1199

end page

  • 208

volume

  • 21

number

  • 10