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The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops
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Journal Article
The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops
2021
Overview
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.
Chromosome rearrangements can be a cause of altered oncogene expression in cancer, such as a 3q26 translocation in some acute myeloid leukemias (AML) that leads to overexpression of EVI1. Here the authors engineer this rearrangement in a cell line and show that EVI1 overexpression is a result of ‘enhancer hijacking’ of the MYC superenhancer, which is facilitated by CTCF-mediated loops.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/35
/ 38/91
/ 42/41
/ 45/15
/ 45/77
/ CCCTC-Binding Factor - genetics
/ CCCTC-Binding Factor - metabolism
/ Chromosomes, Human, Pair 3 - genetics
/ Chromosomes, Human, Pair 8 - genetics
/ CRISPR
/ Docking
/ Enhancer Elements, Genetic - genetics
/ Gene Expression Regulation, Leukemic
/ High-Throughput Nucleotide Sequencing - methods
/ Humanities and Social Sciences
/ Humans
/ In Situ Hybridization, Fluorescence - methods
/ Kinases
/ Leukemia
/ Leukemia, Myeloid - genetics
/ Leukemia, Myeloid - metabolism
/ Leukemia, Myeloid - pathology
/ MDS1 and EVI1 Complex Locus Protein - genetics
/ Mimicry
/ Modules
/ Promoter Regions, Genetic - genetics
/ Proto-Oncogene Proteins c-myc - genetics
/ Science
