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

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

Research output: Contribution to journalArticlepeer-review

Abstract

The 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.

Original languageEnglish
Pages (from-to)7079-7089
Number of pages11
JournalBlood
Volume117
Issue number26
DOIs
StatePublished - 30 Jun 2011

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