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000176967 1001_ $$aOttema, Sophie$$b0
000176967 245__ $$aThe leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops.
000176967 260__ $$a[London]$$bNature Publishing Group UK$$c2021
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000176967 520__ $$aChromosomal rearrangements are a frequent cause of oncogene deregulation in human malignancies. Overexpression of EVI1 is found in a subgroup of acute myeloid leukemia (AML) with 3q26 chromosomal rearrangements, which is often therapy resistant. In AMLs harboring a t(3;8)(q26;q24), we observed the translocation of a MYC super-enhancer (MYC SE) to the EVI1 locus. We generated an in vitro model mimicking a patient-based t(3;8)(q26;q24) using CRISPR-Cas9 technology and demonstrated hyperactivation of EVI1 by the hijacked MYC SE. This MYC SE contains multiple enhancer modules, of which only one recruits transcription factors active in early hematopoiesis. This enhancer module is critical for EVI1 overexpression as well as enhancer-promoter interaction. Multiple CTCF binding regions in the MYC SE facilitate this enhancer-promoter interaction, which also involves a CTCF binding site upstream of the EVI1 promoter. We hypothesize that this CTCF site acts as an enhancer-docking site in t(3;8) AML. Genomic analyses of other 3q26-rearranged AML patient cells point to a common mechanism by which EVI1 uses this docking site to hijack enhancers active in early hematopoiesis.
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000176967 7001_ $$00000-0003-0298-7948$$aMulet-Lazaro, Roger$$b1
000176967 7001_ $$00000-0002-3965-4488$$aErpelinck-Verschueren, Claudia$$b2
000176967 7001_ $$00000-0002-8707-703X$$avan Herk, Stanley$$b3
000176967 7001_ $$aHavermans, Marije$$b4
000176967 7001_ $$aArricibita Varea, Andrea$$b5
000176967 7001_ $$aVermeulen, Michael$$b6
000176967 7001_ $$aBeverloo, H Berna$$b7
000176967 7001_ $$0P:(DE-He78)5120a331b1c28045c8ca6a8b1c73c95f$$aGröschel, Stefan$$b8$$udkfz
000176967 7001_ $$aHaferlach, Torsten$$b9
000176967 7001_ $$aHaferlach, Claudia$$b10
000176967 7001_ $$aJ Wouters, Bas$$b11
000176967 7001_ $$aBindels, Eric$$b12
000176967 7001_ $$00000-0001-7025-8515$$aSmeenk, Leonie$$b13
000176967 7001_ $$aDelwel, Ruud$$b14
000176967 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-021-25862-3$$gVol. 12, no. 1, p. 5679$$n1$$p5679$$tNature Communications$$v12$$x2041-1723$$y2021
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