Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease

Nat Commun. 2012 Jan 10;3:623. doi: 10.1038/ncomms1623.

Abstract

Recent evidence shows increased and decreased expression of Ezh2 in cancer, suggesting a dual role as an oncogene or tumour suppressor. To investigate the mechanism by which Ezh2-mediated H3K27 methylation leads to cancer, we generated conditional Ezh2 knock-in (Ezh2-KI) mice. Here we show that induced Ezh2 haematopoietic expression increases the number and proliferation of repopulating haematopoietic stem cells. Ezh2-KI mice develop myeloproliferative disorder, featuring excessive myeloid expansion in bone marrow and spleen, leukocytosis and splenomegaly. Competitive and serial transplantations demonstrate progressive myeloid commitment of Ezh2-KI haematopoietic stem cells. Transplanted self-renewing haematopoietic stem cells from Ezh2-KI mice induce myeloproliferative disorder, suggesting that the Ezh2 gain-of-function arises in the haematopoietic stem cell pool, and not at later stages of myelopoiesis. At the molecular level, Ezh2 regulates haematopoietic stem cell-specific genes such as Evi-1 and Ntrk3, aberrantly found in haematologic malignancies. These results demonstrate a stem cell-specific Ezh2 oncogenic role in myeloid disorders, and suggest possible therapeutic applications in Ezh2-related haematological malignancies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Animals
  • Cell Proliferation
  • Cell Separation
  • Cell Transplantation
  • DNA-Binding Proteins / biosynthesis*
  • Enhancer of Zeste Homolog 2 Protein
  • Flow Cytometry / methods
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Hematopoietic Stem Cells / cytology*
  • Histones / genetics
  • Immune System
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Models, Genetic
  • Myeloproliferative Disorders / genetics
  • Polycomb Repressive Complex 2
  • Time Factors
  • Transcription Factors / biosynthesis*
  • Transgenes

Substances

  • DNA-Binding Proteins
  • Histones
  • Transcription Factors
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2

Associated data

  • GEO/GSE28369