期刊
CANCER CELL
卷 31, 期 3, 页码 452-465出版社
CELL PRESS
DOI: 10.1016/j.ccell.2017.02.006
关键词
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资金
- Institut National Du Cancer [PLBIO-2014-176]
- Federation Enfants et Sante and Societe Francaise de lutte contre les Cancers et les Leucemies de l'Enfant et l'Adolescent (SFCE: CAMELIAT project)
- Association Laurette Fugain [ALF-2015/13]
- Jose Carreras EHA award [DJCLS-EHA-2009-F-09/02]
- Fondation ARC
- Fondation Gustave Roussy
- SIRIC-SOCRATE [INCa-DGOS-INSERM 6043]
- Fondation pour la Recherche Medicale [FRM-ING20150532273]
- Canceropole Ile de France
- INCa-PlanCancer Soutien pour la formation''
- Fondation de France [FdF-00057925]
- Lady Tata Foundation [R14120LL]
- Gustave Roussy Genomic Core Facility [TA2014]
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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