| Literature DB >> 27604872 |
Ashwin Unnikrishnan1, Yi F Guan2, Yizhou Huang2, Dominik Beck2,3, Julie A I Thoms2, Sofie Peirs4, Kathy Knezevic2, Shiyong Ma2, Inge V de Walle5, Ineke de Jong6, Zara Ali7, Ling Zhong8, Mark J Raftery8, Tom Taghon5, Jonas Larsson6, Karen L MacKenzie7, Pieter Van Vlierberghe4, Jason W H Wong9, John E Pimanda10,11.
Abstract
Aberrant stem cell-like gene regulatory networks are a feature of leukaemogenesis. The ETS-related gene (ERG), an important regulator of normal haematopoiesis, is also highly expressed in T-ALL and acute myeloid leukaemia (AML). However, the transcriptional regulation of ERG in leukaemic cells remains poorly understood. In order to discover transcriptional regulators of ERG, we employed a quantitative mass spectrometry-based method to identify factors binding the 321 bp ERG +85 stem cell enhancer region in MOLT-4 T-ALL and KG-1 AML cells. Using this approach, we identified a number of known binders of the +85 enhancer in leukaemic cells along with previously unknown binders, including ETV6 and IKZF1. We confirmed that ETV6 and IKZF1 were also bound at the +85 enhancer in both leukaemic cells and in healthy human CD34+ haematopoietic stem and progenitor cells. Knockdown experiments confirmed that ETV6 and IKZF1 are transcriptional regulators not just of ERG, but also of a number of genes regulated by a densely interconnected network of seven transcription factors. At last, we show that ETV6 and IKZF1 expression levels are positively correlated with expression of a number of heptad genes in AML and high expression of all nine genes confers poorer overall prognosis.Entities:
Mesh：
Substances：
Year: 2016 PMID： 27604872 PMCID： PMC5159545 DOI： 10.1093/nar/gkw804
Source DB: PubMed Journal: Nucleic Acids Res ISSN： 0305-1048 Impact factor: 16.971