The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops

Sophie Ottema, Roger Mulet-Lazaro, Claudia Erpelinck-Verschueren, Stanley van Herk, Marije Havermans, Andrea Arricibita Varea, Michael Vermeulen, H. Berna Beverloo, Stefan Gröschel, Torsten Haferlach, Claudia Haferlach, Bas Wouters, Eric Bindels, Leonie Smeenk and Ruud Delwel ()
Additional contact information
Sophie Ottema: Erasmus MC Cancer Institute
Roger Mulet-Lazaro: Erasmus MC Cancer Institute
Claudia Erpelinck-Verschueren: Erasmus MC Cancer Institute
Stanley van Herk: Erasmus MC Cancer Institute
Marije Havermans: Erasmus MC Cancer Institute
Andrea Arricibita Varea: Erasmus MC Cancer Institute
Michael Vermeulen: Erasmus MC Cancer Institute
H. Berna Beverloo: Erasmus University Medical Center
Stefan Gröschel: German Cancer Research Center
Torsten Haferlach: Munich Leukemia Laboratory
Claudia Haferlach: Munich Leukemia Laboratory
Bas Wouters: Erasmus MC Cancer Institute
Eric Bindels: Erasmus MC Cancer Institute
Leonie Smeenk: Erasmus MC Cancer Institute
Ruud Delwel: Erasmus MC Cancer Institute

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Chromosomal 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.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-021-25862-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25862-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-25862-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().