The leukemic oncogene EVI1 hijacks a MYC super-enhancer by CTCF-facilitated loops
| Autor: | H. Berna Beverloo, Ruud Delwel, Eric Bindels, Marije Havermans, Sophie Ottema, Stefan Gröschel, Michael Vermeulen, Bas J. Wouters, Torsten Haferlach, Leonie Smeenk, Claudia A.J. Erpelinck-Verschueren, Claudia Haferlach, Roger Mulet-Lazaro, Andrea Arricibita Varea, Stanley van Herk |
|---|---|
| Přispěvatelé: | Hematology, Clinical Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
CCCTC-Binding Factor
Science General Physics and Astronomy Chromosomal translocation Locus (genetics) Biology Article Acute myeloid leukaemia Translocation Genetic General Biochemistry Genetics and Molecular Biology Proto-Oncogene Proteins c-myc 03 medical and health sciences 0302 clinical medicine Super-enhancer hemic and lymphatic diseases Proto-Oncogenes Humans Promoter Regions Genetic Enhancer Transcription factor In Situ Hybridization Fluorescence 030304 developmental biology Gene Rearrangement 0303 health sciences Multidisciplinary Gene Expression Regulation Leukemic High-Throughput Nucleotide Sequencing Myeloid leukemia General Chemistry MDS1 and EVI1 Complex Locus Protein Gene regulation 3. Good health Haematopoiesis Enhancer Elements Genetic Leukemia Myeloid CTCF Karyotyping 030220 oncology & carcinogenesis Acute Disease Cancer research Chromosomes Human Pair 3 K562 Cells Chromosomes Human Pair 8 Protein Binding |
| Zdroj: | Nature Communications, 12(1):5679. Nature Publishing Group Nature Communications, Vol 12, Iss 1, Pp 1-13 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink