| Literature DB >> 28292442 |
Cécile Thirant1, Cathy Ignacimouttou2, Cécile K Lopez3, M'Boyba Diop4, Lou Le Mouël5, Clarisse Thiollier6, Aurélie Siret1, Phillipe Dessen1, Zakia Aid1, Julie Rivière1, Philippe Rameau4, Céline Lefebvre4, Mehdi Khaled4, Guy Leverger7, Paola Ballerini7, Arnaud Petit7, Hana Raslova1, Catherine L Carmichael8, Benjamin T Kile8, Eric Soler9, John D Crispino10, Christian Wichmann11, Françoise Pflumio9, Jürg Schwaller12, William Vainchenker1, Camille Lobry1, Nathalie Droin13, Olivier A Bernard14, Sébastien Malinge1, Thomas Mercher15.
Abstract
Chimeric transcription factors are a hallmark of human leukemia, but the molecular mechanisms by which they block differentiation and promote aberrant self-renewal remain unclear. Here, we demonstrate that the ETO2-GLIS2 fusion oncoprotein, which is found in aggressive acute megakaryoblastic leukemia, confers megakaryocytic identity via the GLIS2 moiety while both ETO2 and GLIS2 domains are required to drive increased self-renewal properties. ETO2-GLIS2 directly binds DNA to control transcription of associated genes by upregulation of expression and interaction with the ETS-related ERG protein at enhancer elements. Importantly, specific interference with ETO2-GLIS2 oligomerization reverses the transcriptional activation at enhancers and promotes megakaryocytic differentiation, providing a relevant interface to target in this poor-prognosis pediatric leukemia.Entities:
Keywords: AMKL; CBFA2T3; CRISPR; ChIP; ERG; GLIS; enhancer; leukemia; pediatric; transcription factor
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Year: 2017 PMID： 28292442 DOI： 10.1016/j.ccell.2017.02.006
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743