Lineage-specific function of Engrailed-2 in the progression of chronic myelogenous leukemia to T-cell blast crisis

Cell Cycle. 2014;13(11):1717-26. doi: 10.4161/cc.28629. Epub 2014 Mar 25.

Abstract

In hematopoietic malignancies, oncogenic alterations interfere with cellular differentiation and lead to tumoral development. Identification of the proteins regulating differentiation is essential to understand how they are altered in malignancies. Chronic myelogenous leukemia (CML) is a biphasic disease initiated by an alteration taking place in hematopoietic stem cells. CML progresses to a blast crisis (BC) due to a secondary differentiation block in any of the hematopoietic lineages. However, the molecular mechanisms of CML evolution to T-cell BC remain unclear. Here, we have profiled the changes in DNA methylation patterns in human samples from BC-CML, in order to identify genes whose expression is epigenetically silenced during progression to T-cell lineage-specific BC. We have found that the CpG-island of the ENGRAILED-2 (EN2) gene becomes methylated in this progression. Afterwards, we demonstrate that En2 is expressed during T-cell development in mice and humans. Finally, we further show that genetic deletion of En2 in a CML transgenic mouse model induces a T-cell lineage BC that recapitulates human disease. These results identify En2 as a new regulator of T-cell differentiation whose disruption induces a malignant T-cell fate in CML progression, and validate the strategy used to identify new developmental regulators of hematopoiesis.

Keywords: DNA methylation; T-cell development; blast crisis; chronic myelogenous leukemia; engrailed-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blast Crisis / metabolism*
  • Cell Differentiation / immunology*
  • CpG Islands / genetics
  • DNA Methylation / genetics
  • DNA Primers / genetics
  • Disease Progression
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic / physiology*
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Mice
  • Mice, Transgenic
  • Microarray Analysis
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes / immunology*

Substances

  • DNA Primers
  • Homeodomain Proteins
  • Nerve Tissue Proteins
  • engrailed 2 protein