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

• DOI: 10.1016/j.ccell.2017.02.006
• Publication Date: 2017-03-13T16:17:11Z
• Authors: Cécile Thirant; Cathy Ignacimouttou; Cécile K. Lopez; M’Boyba Diop; Lou Le Mouël; Clarisse Thiollier; Aurélie Siret; Phillipe Dessen; Zakia Aid; Julie Rivière; Philippe Rameau; Céline Lefebvre; Mehdi Khaled; Guy Leverger; Paola Ballerini; Arnaud Petit; Hana Raslova; Catherine L. Carm...; Benjamin T. Kile; Eric Soler; John D. Crispino; Christian Wichmann; Françoise Pflumio; Jürg Schwaller; William Vainchenker; Camille Lobry; Nathalie Droin; Olivier A. Bernard; Sébastien Malinge; Thomas Mercher
• Keywords: Transcriptional Activation; 0301 basic medicine; Oncogene Proteins, Fusion; Cell Differentiation; Mice; 03 medical and health sciences; Transcriptional activation; Enhancer Elements, Genetic; Transcriptional Regulator ERG; Leukemia, Megakaryoblastic, Acute; transcriptional regulator ERG; Animals; Humans; GATA1 Transcription Factor; Child

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.