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

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.

• Authors: Julie A I Thoms, Yehudit Birger, Sam Foster, Kathy Knezevic, Yael Kirschenbaum, Vashe Chandrakanthan, Georg Jonquieres, Dominik Spensberger, Jason W Wong, S Helen Oram, Sarah J Kinston, Yoram Groner, Richard Lock, Karen L MacKenzie, Berthold Göttgens, Shai Izraeli, John E Pimanda
• Journal: Blood (Blood) Vol. 117 Issue 26 Pg. 7079-89 (Jun 30 2011) ISSN: 1528-0020 [Electronic] United States
• PMID: 21536859 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, metabolism, pathology)
• Promoter Regions, Genetic
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-vav (genetics, metabolism)
• RNA, Messenger (metabolism)
• Sequence Alignment
• Survival Analysis
• T-Cell Acute Lymphocytic Leukemia Protein 1
• T-Lymphocytes (metabolism, pathology)
• Trans-Activators (antagonists & inhibitors, chemistry, genetics, metabolism)
• Transcriptional Regulator ERG