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

作者：Thoms Julie A I; Birger Yehudit; Foster Sam; Knezevic Kathy; Kirschenbaum Yael; Chandrakanthan Vashe; Jonquieres Georg; Spen**erger Dominik; Wong Jason W; Oram S Helen; Kinston Sarah J; Groner Yoram; Lock Richard; MacKenzie Karen L; Goettgens Berthold; Izraeli Shai; Pimanda John E^*

来源：Blood, 2011, 117(26): 7079-7089.

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. (Blood. 2011;117(26):7079-7089)

• 出版日期2011-6-30
• 单位河北医科大学