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

• Published in: Blood 2011-06, Vol.117 (26), p.7079-7089
• Main Authors: Thoms, Julie A.I., Birger, Yehudit, Foster, Sam, Knezevic, Kathy, Kirschenbaum, Yael, Chandrakanthan, Vashe, Jonquieres, Georg, Spensberger, Dominik, Wong, Jason W., Oram, S. Helen, Kinston, Sarah J., Groner, Yoram, Lock, Richard, MacKenzie, Karen L., Göttgens, Berthold, Izraeli, Shai, Pimanda, John E.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Base Sequence; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Leukemic; Gene Knockdown Techniques; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; LIM Domain Proteins; Medical sciences; 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
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-12-317990

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.