Genetic inactivation of the polycomb repressive complex 2 in T cell acute lymphoblastic leukemia

Nat Med. 2012 Feb 6;18(2):298-301. doi: 10.1038/nm.2651.

Abstract

T cell acute lymphoblastic leukemia (T-ALL) is an immature hematopoietic malignancy driven mainly by oncogenic activation of NOTCH1 signaling. In this study we report the presence of loss-of-function mutations and deletions of the EZH2 and SUZ12 genes, which encode crucial components of the Polycomb repressive complex 2 (PRC2), in 25% of T-ALLs. To further study the role of PRC2 in T-ALL, we used NOTCH1-dependent mouse models of the disease, as well as human T-ALL samples, and combined locus-specific and global analysis of NOTCH1-driven epigenetic changes. These studies demonstrated that activation of NOTCH1 specifically induces loss of the repressive mark Lys27 trimethylation of histone 3 (H3K27me3) by antagonizing the activity of PRC2. These studies suggest a tumor suppressor role for PRC2 in human leukemia and suggest a hitherto unrecognized dynamic interplay between oncogenic NOTCH1 and PRC2 function for the regulation of gene expression and cell transformation.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Enhancer of Zeste Homolog 2 Protein
  • Epigenesis, Genetic / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Silencing / physiology
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Mice
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Polycomb Repressive Complex 2
  • Polycomb-Group Proteins
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • NOTCH1 protein, human
  • Nuclear Proteins
  • Polycomb-Group Proteins
  • Receptor, Notch1
  • Repressor Proteins
  • SUZ12 protein, human
  • Suz12 protein, mouse
  • Transcription Factors
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Polycomb Repressive Complex 2

Associated data

  • GEO/GSE34554
  • GEO/GSE34954