The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops.
Acute Disease
CCCTC-Binding Factor
/ genetics
Chromosomes, Human, Pair 3
/ genetics
Chromosomes, Human, Pair 8
/ genetics
Enhancer Elements, Genetic
/ genetics
Gene Expression Regulation, Leukemic
Gene Rearrangement
High-Throughput Nucleotide Sequencing
/ methods
Humans
In Situ Hybridization, Fluorescence
/ methods
K562 Cells
Karyotyping
Leukemia, Myeloid
/ genetics
MDS1 and EVI1 Complex Locus Protein
/ genetics
Promoter Regions, Genetic
/ genetics
Protein Binding
Proto-Oncogene Proteins c-myc
/ genetics
Proto-Oncogenes
/ genetics
Translocation, Genetic
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
28 09 2021
28 09 2021
Historique:
received:
10
06
2021
accepted:
02
09
2021
entrez:
29
9
2021
pubmed:
30
9
2021
medline:
26
10
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34584081
doi: 10.1038/s41467-021-25862-3
pii: 10.1038/s41467-021-25862-3
pmc: PMC8479123
doi:
Substances chimiques
CCCTC-Binding Factor
0
MDS1 and EVI1 Complex Locus Protein
0
MECOM protein, human
0
Proto-Oncogene Proteins c-myc
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5679Informations de copyright
© 2021. The Author(s).
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