EZH2 Is Required for Germinal Center Formation and Somatic EZH2 Mutations Promote Lymphoid Transformation

Cancer Cell. 2013 May 13;23(5):677-92. doi: 10.1016/j.ccr.2013.04.011.

Abstract

The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B cells and targeted by somatic mutations in B cell lymphomas. Here, we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GC B cell (GCB)-type diffuse large B cell lymphomas (DLBCLs) are mostly addicted to EZH2 but not the more differentiated activated B cell (ABC)-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting.

Publication types

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

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism*
  • Cell Differentiation
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Enhancer of Zeste Homolog 2 Protein
  • Gene Deletion
  • Gene Expression Regulation, Neoplastic
  • Germinal Center / drug effects
  • Germinal Center / metabolism*
  • Histones / metabolism
  • Methylation
  • Mice
  • Mutation*
  • Polycomb Repressive Complex 2 / genetics
  • Polycomb Repressive Complex 2 / metabolism
  • Polycomb Repressive Complex 2 / physiology*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / physiology

Substances

  • Histones
  • Proto-Oncogene Proteins c-bcl-2
  • Bcl2 protein, mouse
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Polycomb Repressive Complex 2

Associated data

  • GEO/GSE23501
  • GEO/GSE45982