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

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 leukemi...

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Bibliographic Details
Published in:Cancer cell 2017-03, Vol.31 (3), p.452-465
Main Authors: Thirant, Cécile, Ignacimouttou, Cathy, Lopez, Cécile K., Diop, M’Boyba, Le Mouël, Lou, Thiollier, Clarisse, Siret, Aurélie, Dessen, Phillipe, Aid, Zakia, Rivière, Julie, Rameau, Philippe, Lefebvre, Céline, Khaled, Mehdi, Leverger, Guy, Ballerini, Paola, Petit, Arnaud, Raslova, Hana, Carmichael, Catherine L., Kile, Benjamin T., Soler, Eric, Crispino, John D., Wichmann, Christian, Pflumio, Françoise, Schwaller, Jürg, Vainchenker, William, Lobry, Camille, Droin, Nathalie, Bernard, Olivier A., Malinge, Sébastien, Mercher, Thomas
Format: Article
Language:English
Subjects:
AMKL
Animals
CBFA2T3
Cell Differentiation
Child
ChIP
CRISPR
enhancer
Enhancer Elements, Genetic
ERG
GATA1 Transcription Factor - genetics
GLIS
Humans
leukemia
Leukemia, Megakaryoblastic, Acute - pathology
Mice
Oncogene Proteins, Fusion - chemistry
Oncogene Proteins, Fusion - physiology
pediatric
transcription factor
Transcriptional Activation
Transcriptional Regulator ERG - physiology
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Summary: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. [Display omitted] •The GLIS2 moiety of ETO2-GLIS2 oncoprotein controls the megakaryocytic identity•Human AMKL oncogenes often cause GATA/ETS functional imbalance•ETO2-GLIS2 binds enhancer regions together with the ERG transcription factor•The NHR2 interface is essential for maintenance of ETO2-GLIS2-driven leukemia Thirant et al. show that the ETO2-GLIS2 fusion protein found in acute megakaryoblastic leukemia confers megakaryocytic identity via the GLIS2 moiety, but requires both ETO2 and GLIS2 domains to drive self-renewal. Disruption of ETO2-GLIS2 oligomerization inhibits the maintenance of ETO2-GLIS2+ human AMKL blasts.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccell.2017.02.006