Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Base Sequence
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Line, Tumor
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Cell Proliferation
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Cells, Cultured
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DNA-Binding Proteins / metabolism
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Gene Expression Regulation, Leukemic*
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Gene Knockdown Techniques
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Humans
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LIM Domain Proteins
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Metalloproteins / metabolism
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Mice
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Mice, Transgenic
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Molecular Sequence Data
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Neoplasm Proteins / metabolism
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Neoplasm Transplantation
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Promoter Regions, Genetic
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-vav / genetics
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Proto-Oncogene Proteins c-vav / metabolism
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RNA, Messenger / metabolism
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Sequence Alignment
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Survival Analysis
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T-Cell Acute Lymphocytic Leukemia Protein 1
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T-Lymphocytes / metabolism*
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T-Lymphocytes / pathology
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Trans-Activators / antagonists & inhibitors
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Trans-Activators / chemistry
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Transcriptional Regulator ERG
Substances
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Adaptor Proteins, Signal Transducing
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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ERG protein, human
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LIM Domain Proteins
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LMO2 protein, human
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LYL1 protein, human
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Metalloproteins
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Neoplasm Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-vav
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RNA, Messenger
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T-Cell Acute Lymphocytic Leukemia Protein 1
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Trans-Activators
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Transcriptional Regulator ERG
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TAL1 protein, human