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

Thirant, C.; Ignacimouttou, C.; Lopez, C. K.; Diop, M.; Le Mouel, L.; Thiollier, C.; Siret, A.; Dessen, P.; Aid, Z.; Riviere, J.; Rameau, P.; Lefebvre, C.; Khaled, M.; Leverger, G.; Ballerini, P.; Petit, A.; Raslova, H.; Carmichael, C. L.; Kile, B. T.; Soler, E.; Crispino, J. D.; Wichmann, C.; Pflumio, F.; Schwaller, J.; Vainchenker, W.; Lobry, C.; Droin, N.; Bernard, O. A.; Malinge, S.; Mercher, T.

Cancer Cell. 2017 Mar 16; 31(3):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.

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