title: 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.affiliation: Lowy Cancer Research Centre and the Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.
authors.forename: Julie A I
authors.initials: JA
authors.lastname: Thoms
authors.forename: Yehudit
authors.initials: Y
authors.lastname: Birger
authors.forename: Sam
authors.initials: S
authors.lastname: Foster
authors.forename: Kathy
authors.initials: K
authors.lastname: Knezevic
authors.forename: Yael
authors.initials: Y
authors.lastname: Kirschenbaum
authors.forename: Vashe
authors.initials: V
authors.lastname: Chandrakanthan
authors.forename: Georg
authors.initials: G
authors.lastname: Jonquieres
authors.forename: Dominik
authors.initials: D
authors.lastname: Spensberger
authors.forename: Jason W
authors.initials: JW
authors.lastname: Wong
authors.forename: S Helen
authors.initials: SH
authors.lastname: Oram
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Kinston
authors.forename: Yoram
authors.initials: Y
authors.lastname: Groner
authors.forename: Richard
authors.initials: R
authors.lastname: Lock
authors.forename: Karen L
authors.initials: KL
authors.lastname: MacKenzie
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.forename: Shai
authors.initials: S
authors.lastname: Izraeli
authors.forename: John E
authors.initials: JE
authors.lastname: Pimanda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D006801:Humans; D060588:LIM Domain Proteins; D008667:Metalloproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016415:Sequence Alignment; D016019:Survival Analysis; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D008667:Metalloproteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D012333:RNA, Messenger; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C072312:ERG protein, human; C085117:LMO2 protein, human; C086541:LYL1 protein, human; C067143:TAL1 protein, human