title: ETO2-GLIS2 Hijacks Transcriptional Complexes to Drive Cellular Identity and Self-Renewal in Pediatric Acute Megakaryoblastic Leukemia.
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.
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Gustave Roussy, 94800 Villejuif, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Thirant
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Université Paris Diderot, 75013 Paris, France.
authors.forename: Cathy
authors.initials: C
authors.lastname: Ignacimouttou
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Université Paris-Sud, 91405 Orsay, France.
authors.forename: Cécile K
authors.initials: CK
authors.lastname: Lopez
authors.affiliation: Gustave Roussy, 94800 Villejuif, France.
authors.forename: M'Boyba
authors.initials: M
authors.lastname: Diop
authors.affiliation: Gustave Roussy, 94800 Villejuif, France; Université Paris-Sud, 91405 Orsay, France.
authors.forename: Lou
authors.initials: L
authors.lastname: Le Mouël
authors.affiliation: Gustave Roussy, 94800 Villejuif, France; Université Paris Diderot, 75013 Paris, France.
authors.forename: Clarisse
authors.initials: C
authors.lastname: Thiollier
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Gustave Roussy, 94800 Villejuif, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Siret
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Gustave Roussy, 94800 Villejuif, France.
authors.forename: Phillipe
authors.initials: P
authors.lastname: Dessen
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Gustave Roussy, 94800 Villejuif, France.
authors.forename: Zakia
authors.initials: Z
authors.lastname: Aid
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Gustave Roussy, 94800 Villejuif, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Rivière
authors.affiliation: Gustave Roussy, 94800 Villejuif, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rameau
authors.affiliation: Gustave Roussy, 94800 Villejuif, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Lefebvre
authors.affiliation: Gustave Roussy, 94800 Villejuif, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Khaled
authors.affiliation: Hôpital Trousseau, AP-HP, 75012 Paris, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Leverger
authors.affiliation: Hôpital Trousseau, AP-HP, 75012 Paris, France.
authors.forename: Paola
authors.initials: P
authors.lastname: Ballerini
authors.affiliation: Hôpital Trousseau, AP-HP, 75012 Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Petit
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Gustave Roussy, 94800 Villejuif, France.
authors.forename: Hana
authors.initials: H
authors.lastname: Raslova
authors.affiliation: Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Carmichael
authors.affiliation: Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
authors.affiliation: INSERM UMR967, 92265 Fontenay-aux-Roses, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Soler
authors.affiliation: Division of Hematology/Oncology, Northwestern University, Chicago, IL 60611, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Crispino
authors.affiliation: Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig-Maximilian University Hospital, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Wichmann
authors.affiliation: INSERM UMR967, 92265 Fontenay-aux-Roses, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Pflumio
authors.affiliation: University Children's Hospital Beider Basel (UKBB), Departement of Biomedicine, University of Basel, 4031 Basel, Switzerland.
authors.forename: Jürg
authors.initials: J
authors.lastname: Schwaller
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Gustave Roussy, 94800 Villejuif, France.
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Gustave Roussy, 94800 Villejuif, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Lobry
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Gustave Roussy, 94800 Villejuif, France; Université Paris-Sud, 91405 Orsay, France; INSERM U523, CNRS UMS3655, Gustave Roussy, 94800 Villejuif, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Droin
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Gustave Roussy, 94800 Villejuif, France; Université Paris-Sud, 91405 Orsay, France.
authors.forename: Olivier A
authors.initials: OA
authors.lastname: Bernard
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Gustave Roussy, 94800 Villejuif, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Malinge
authors.affiliation: INSERM U1170, Equipe Labellisée Ligue Contre le Cancer, Gustave Roussy Institute, 39 rue Camille Desmoulins, 94800 Villejuif, France; Gustave Roussy, 94800 Villejuif, France; Université Paris Diderot, 75013 Paris, France; Université Paris-Sud, 91405 Orsay, France. Electronic address: thomas.mercher@inserm.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mercher
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002648:Child; D004742:Enhancer Elements, Genetic; D050982:GATA1 Transcription Factor / Q000235:genetics; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000473:pathology*; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000502:physiology*; D015533:Transcriptional Activation; D000071230:Transcriptional Regulator ERG / Q000502:physiology
chemical_list: C072312:ERG protein, human; C577497:ETO2-GLIS2 fusion protein, human; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D015514:Oncogene Proteins, Fusion; D000071230:Transcriptional Regulator ERG
keywords: AMKL; CBFA2T3; CRISPR; ChIP; ERG; GLIS; enhancer; leukemia; pediatric; transcription factor