ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia

Thirant, Cecile; Ignacimouttou, Cathy; Lopez, Cecile K.; Diop, M'Boyba; Le Mouel, Lou; Thiollier, Clarisse; Siret, Aurelie; Dessen, Phillipe; Aid, Zakia; Riviere, Julie; Rameau, Philippe; Lefebvre, Ce ' Line; Khaled, Mehdi; Leverger, Guy; Ballerini, Paola; Petit, Arnaud; Raslova, Hana; Carmichael, Catherine L.; Kile, Benjamin T.; Soler, Eric; Crispino, John D.; Wichmann, Christian; Pflumio, Francoise; Schwaller, Jurg; Vainchenker, William; Lobry, Camille; Droin, Nathalie; Bernard, Olivier A.; Malinge, Sebastien und Mercher, Thomas (2017): ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia. In: Cancer Cell, Bd. 31, Nr. 3: S. 452-465

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1535-6108
• Sprache: Englisch