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

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dc.contributor.authorThoms, J.A.I.
dc.contributor.authorBirger, Y.
dc.contributor.authorFoster, S.
dc.contributor.authorKnezevic, K.
dc.contributor.authorKirschenbaum, Y.
dc.contributor.authorChandrakanthan, V.
dc.contributor.authorJonquieres, G.
dc.contributor.authorSpensberger, D.
dc.contributor.authorWong, J.W.
dc.contributor.authorOram, S.H.
dc.contributor.authorKinston, S.J.
dc.contributor.authorGroner, Y.
dc.contributor.authorLock, R.
dc.contributor.authorMacKenzie, K.L.
dc.contributor.authorGöttgens, B.
dc.contributor.authorIzraeli, S.
dc.contributor.authorPimanda, J.E.
dc.date.issued2011
dc.description.abstractThe 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.
dc.description.statementofresponsibilityJulie 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, and John E. Pimanda
dc.identifier.citationBlood, 2011; 117(26):7079-7089
dc.identifier.doi10.1182/blood-2010-12-317990
dc.identifier.issn0006-4971
dc.identifier.issn1528-0020
dc.identifier.orcidChandrakanthan, V. [0000-0002-4314-5029]
dc.identifier.urihttps://hdl.handle.net/2440/145949
dc.language.isoen
dc.publisherAmerican Society of Hematology (ASH Publications)
dc.relation.grantNHMRC
dc.relation.grantARC
dc.rights© 2011 by The American Society of Hematology
dc.source.urihttps://doi.org/10.1182/blood-2010-12-317990
dc.subjectEts-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/progenitors
dc.subject.meshT-Lymphocytes
dc.subject.meshCells, Cultured
dc.subject.meshCell Line, Tumor
dc.subject.meshAnimals
dc.subject.meshMice, Transgenic
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshAdaptor Proteins, Signal Transducing
dc.subject.meshDNA-Binding Proteins
dc.subject.meshTrans-Activators
dc.subject.meshMetalloproteins
dc.subject.meshNeoplasm Proteins
dc.subject.meshProto-Oncogene Proteins
dc.subject.meshRNA, Messenger
dc.subject.meshSurvival Analysis
dc.subject.meshSequence Alignment
dc.subject.meshNeoplasm Transplantation
dc.subject.meshCell Proliferation
dc.subject.meshGene Expression Regulation, Leukemic
dc.subject.meshBase Sequence
dc.subject.meshMolecular Sequence Data
dc.subject.meshProto-Oncogene Proteins c-vav
dc.subject.meshBasic Helix-Loop-Helix Transcription Factors
dc.subject.meshPrecursor T-Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.meshPromoter Regions, Genetic
dc.subject.meshGene Knockdown Techniques
dc.subject.meshLIM Domain Proteins
dc.subject.meshTranscriptional Regulator ERG
dc.subject.meshT-Cell Acute Lymphocytic Leukemia Protein 1
dc.titleERG promotes T-acute lymphoblastic leukemia and is transcriptionally regulated in leukemic cells by a stem cell enhancer
dc.typeJournal article
pubs.publication-statusPublished

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