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A Single Oncogenic Enhancer Rearrangement Causes Concomitant EVI1 and GATA2 Deregulation in Leukemia
Open accessAbstract
Chromosomal rearrangements without gene fusions have been implicated in leukemogenesis by causing deregulation of proto-oncogenes via relocation of cryptic regulatory DNA elements. AML with inv(3)/t(3;3) is associated with aberrant expression of the stem-cell regulator EVI1. Applying functional genomics and genome-engineering, we demonstrate that both 3q rearrangements reposition a distal GATA2 enhancer to ectopically activate EVI1 and simultaneously confer GATA2 functional haploinsufficiency, previously identified as the cause of sporadic familial AML/MDS and MonoMac/Emberger syndromes. Genomic excision of the ectopic enhancer restored EVI1 silencing and led to growth inhibition and differentiation of AML cells, which could be replicated by pharmacologic BET inhibition. Our data show that structural rearrangements involving the chromosomal repositioning of a single enhancer can cause deregulation of two unrelated distal genes, with cancer as the outcome.
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“Very recently, AML has also emerged as such an “enhanceropathy”51.”
From Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia (2015) · cites this paper as [51]
In the citing paper
“proto-oncogene MECOM activation due to an inversion between TADs in acute myeloid leukemia cells, which facilitates tumor formation14.”
From Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer (2020) · cites this paper as [14]
In the citing paper
“Furthermore, chromosomal rearrangements such as translocations or deletions which activate oncogenes also disrupt insulated neighborhoods around those genes without altering the sequence of the gene itself (Groschel et al., 2014; Hnisz et al., 2016).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Groschel et al., 2014
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Metadata
- Authors
- Gröschel, S., Sanders, M. A., Hoogenboezem, R., de Wit, E., Bouwman, B. A. M., Erpelinck, C., van der Velden, V. H. J., Havermans, M., Avellino, R., van Lom, K., Rombouts, E. J., van Duin, M., Döhner, K., Beverloo, H. B., Bradner, J. E., Döhner, H., Löwenberg, B., Valk, P. J. M., Bindels, E. M. J., de Laat, W., & Delwel, R.
- Affiliations
- Erasmus MC (NL)
- University Medical Center Utrecht (NL)
- University Hospital Ulm (DE)
- Harvard University (US)
- Corresponding author
- Delwel, Ruud
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 157
- Issue
- 2
- Pages
- 369-381
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1978902427
- Cited by
- 687
- References
- 51
- Citations by year
- 2026: 29 · 2025: 45 · 2024: 42 · 2023: 72 · 2022: 55 · 2021: 69 · 2020: 66 · 2019: 62 · 2018: 59 · 2017: 65 · 2016: 59 · 2015: 45 · 2014: 15
- FWCI
- 43.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Association for International Cancer Research
- Deutsche Forschungsgemeinschaft (GR 3955/1-1)
- Lady Tata Memorial Trust
- European Hematology Association
- Center for Translational Molecular Medicine (GR03O-102)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- EVI1, GATA2, acute myeloid leukemia, haploinsufficiency, BET inhibition, leukemia cell differentiation, leukemogenesis
- MeSH terms
- MDS1 and EVI1 Complex Locus Protein, Chromosomes, Human, Pair 3, DNA-Binding Proteins, Enhancer Elements, Genetic, Humans, Chromosome Inversion, Myelodysplastic Syndromes, Promoter Regions, Genetic, Proto-Oncogenes, Transcription Factors, Translocation, Genetic, Leukemia, Myeloid, Acute, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, GATA2 Transcription Factor
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