Thoms, J.A.I.Birger, Y.Foster, S.Knezevic, K.Kirschenbaum, Y.Chandrakanthan, V.Jonquieres, G.Spensberger, D.Wong, J.W.Oram, S.H.Kinston, S.J.Groner, Y.Lock, R.MacKenzie, K.L.Göttgens, B.Izraeli, S.Pimanda, J.E.2025-07-152025-07-152011Blood, 2011; 117(26):7079-70890006-49711528-0020https://hdl.handle.net/2440/145949The Ets-related gene (ERG) is an Etstranscription factor required for normal blood stem cell development. ERG expression is down-regulated during early Tlymphopoiesis 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‾ doublenegative 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.en© 2011 by The American Society of HematologyEts-related gene (ERG); blood stem cell development; Tlymphopoiesis; T-acute lymphoblastic leukemia (T-ALL); MOLT4 T-ALL cells; T-cell oncogenes; ERG +85 enhancer; adult bone marrow stem/progenitorsT-LymphocytesCells, CulturedCell Line, TumorAnimalsMice, TransgenicHumansMiceAdaptor Proteins, Signal TransducingDNA-Binding ProteinsTrans-ActivatorsMetalloproteinsNeoplasm ProteinsProto-Oncogene ProteinsRNA, MessengerSurvival AnalysisSequence AlignmentNeoplasm TransplantationCell ProliferationGene Expression Regulation, LeukemicBase SequenceMolecular Sequence DataProto-Oncogene Proteins c-vavBasic Helix-Loop-Helix Transcription FactorsPrecursor T-Cell Lymphoblastic Leukemia-LymphomaPromoter Regions, GeneticGene Knockdown TechniquesLIM Domain ProteinsTranscriptional Regulator ERGT-Cell Acute Lymphocytic Leukemia Protein 1Journal article10.1182/blood-2010-12-3179902024-05-12632226Chandrakanthan, V. [0000-0002-4314-5029]