ERG promotes T-acute lymphoblastic leukemia and is transcriptionally regulated in leukemic cells by a stem cell enhancer

Blood. 2011 Jun 30;117(26):7079-89. doi: 10.1182/blood-2010-12-317990. Epub 2011 May 2.


The Ets-related gene (ERG) is an Ets-transcription factor required for normal blood stem cell development. ERG expression is down-regulated during early T-lymphopoiesis but maintained in T-acute lymphoblastic leukemia (T-ALL), where it is recognized as an independent risk factor for adverse outcome. However, it is unclear whether ERG is directly involved in the pathogenesis of T-ALL and how its expression is regulated. Here we demonstrate that transgenic expression of ERG causes T-ALL in mice and that its knockdown reduces the proliferation of human MOLT4 T-ALL cells. We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. This enhancer is not active in normal T cells but in transgenic mice targets expression to fetal liver c-kit(+) cells, adult bone marrow stem/progenitors and early CD4(-)CD8(-) double-negative thymic progenitors. Taken together, these data illustrate that ERG promotes T-ALL and that failure to extinguish activity of stem cell enhancers associated with regulatory transcription factors such as ERG can contribute to the development of leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Gene Expression Regulation, Leukemic*
  • Gene Knockdown Techniques
  • Humans
  • LIM Domain Proteins
  • Metalloproteins / metabolism
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Neoplasm Proteins / metabolism
  • Neoplasm Transplantation
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-vav / genetics
  • Proto-Oncogene Proteins c-vav / metabolism
  • RNA, Messenger / metabolism
  • Sequence Alignment
  • Survival Analysis
  • T-Cell Acute Lymphocytic Leukemia Protein 1
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / pathology
  • Trans-Activators / antagonists & inhibitors
  • Trans-Activators / chemistry
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcriptional Regulator ERG


  • Adaptor Proteins, Signal Transducing
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • ERG protein, human
  • LIM Domain Proteins
  • LMO2 protein, human
  • LYL1 protein, human
  • Metalloproteins
  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-vav
  • RNA, Messenger
  • T-Cell Acute Lymphocytic Leukemia Protein 1
  • Trans-Activators
  • Transcriptional Regulator ERG
  • TAL1 protein, human