The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis
Open accessAbstract
DNA methylation is tightly regulated throughout mammalian development, and altered DNA methylation patterns are a general hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in hematological disorders, including acute myeloid leukemia (AML), and has been suggested to protect CG dinucleotide (CpG) islands and promoters from aberrant DNA methylation. In this study, we present a novel Tet2-dependent leukemia mouse model that closely recapitulates gene expression profiles and hallmarks of human AML1-ETO-induced AML. Using this model, we show that the primary effect of Tet2 loss in preleukemic hematopoietic cells is progressive and widespread DNA hypermethylation affecting up to 25% of active enhancer elements. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner but increases relative to population doublings. We confirmed this specific enhancer hypermethylation phenotype in human AML patients with TET2 mutations. Analysis of immediate gene expression changes reveals rapid deregulation of a large number of genes implicated in tumorigenesis, including many down-regulated tumor suppressor genes. Hence, we propose that TET2 prevents leukemic transformation by protecting enhancers from aberrant DNA methylation and that it is the combined silencing of several tumor suppressor genes in TET2 mutated hematopoietic cells that contributes to increased stem cell proliferation and leukemogenesis.
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“Compound mutant cells also exhibited greater serial colony-forming activity than Tet2KO cells, which showed extended serial replating activity, in line with past reports (17, 32).”
From PU.1-Dependent Enhancer Inhibition Separates Tet2 -Deficient Hematopoiesis from Malignant Transformation (2022) · cites this paper as [32]
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“Consistently, TET2-mutant immature and myeloid cells present with hypermethylation of active enhancers and perturbed TF activity (28, 32, 53).”
From PU.1-Dependent Enhancer Inhibition Separates Tet2 -Deficient Hematopoiesis from Malignant Transformation (2022) · cites this paper as [32]
Experimental — accuracy not yet measuredIn the citing paper
“Hypermethylation at enhancer elements coincides with leukaemogenesis in haematopoietic progenitor cells of TET2−/− mice expressing the AML–ETO9a fusion.40”
From Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia (2018) · cites this paper as [40]
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Additional file 5 of Vitamin C boosts DNA demethylation in TET2 germline mutation carriers
Taira, A., Palin, K., Kuosmanen, A., Välimäki, N., Kuittinen, O. M., Kuismin, O., Kaasinen, E., Rajamäki, K., & Aaltonen, L. A. (2024) · Figshare · doi:10.6084/m9.figshare.26561383
Nirgude, S., Desai, S. S., & Choudhary, B. (2024) · Figshare · doi:10.6084/m9.figshare.26551000
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Additional file 4 of Vitamin C boosts DNA demethylation in TET2 germline mutation carriers
Taira, A., Palin, K., Kuosmanen, A., Välimäki, N., Kuittinen, O. M., Kuismin, O., Kaasinen, E., Rajamäki, K., & Aaltonen, L. A. (2024) · Figshare · doi:10.6084/m9.figshare.26561380
Nirgude, S., Desai, S. S., & Choudhary, B. (2024) · Figshare · doi:10.6084/m9.figshare.26551003
Additional file 2 of Vitamin C boosts DNA demethylation in TET2 germline mutation carriers
Taira, A., Palin, K., Kuosmanen, A., Välimäki, N., Kuittinen, O. M., Kuismin, O., Kaasinen, E., Rajamäki, K., & Aaltonen, L. A. (2024) · Figshare · doi:10.6084/m9.figshare.26561374
Additional file 6 of Vitamin C boosts DNA demethylation in TET2 germline mutation carriers
Taira, A., Palin, K., Kuosmanen, A., Välimäki, N., Kuittinen, O. M., Kuismin, O., Kaasinen, E., Rajamäki, K., & Aaltonen, L. A. (2024) · Figshare · doi:10.6084/m9.figshare.26561386
Additional file 3 of Vitamin C boosts DNA demethylation in TET2 germline mutation carriers
Taira, A., Palin, K., Kuosmanen, A., Välimäki, N., Kuittinen, O. M., Kuismin, O., Kaasinen, E., Rajamäki, K., & Aaltonen, L. A. (2024) · Figshare · doi:10.6084/m9.figshare.26561377
Alberge, J.-B., Magrangeas, F., Wagner, M., Denié, S., Guérin‐Charbonnel, C., Campion, L., Attal, M., Avet‐Loiseau, H., Carell, T., Moreau, P., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13181443
Additional file 1 of Vitamin C boosts DNA demethylation in TET2 germline mutation carriers
Taira, A., Palin, K., Kuosmanen, A., Välimäki, N., Kuittinen, O. M., Kuismin, O., Kaasinen, E., Rajamäki, K., & Aaltonen, L. A. (2024) · Figshare · doi:10.6084/m9.figshare.26561371
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Metadata
- Authors
- Rasmussen, K. D., Jia, G., Johansen, J. V., Pedersen, M. T., Rapin, N., Bagger, F. O., Porse, B. T., Bernard, O. A., Christensen, J., & Helin, K.
- Affiliations
- University of Copenhagen (DK)
- Inserm (FR)
- Corresponding author
- Helin, Kristian
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2015-04-17
- Volume
- 29
- Issue
- 9
- Pages
- 910-922
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC4421980
- OpenAlex
- W2169012047
- Cited by
- 270
- References
- 53
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 21 · 2023: 19 · 2022: 23 · 2021: 23 · 2020: 39 · 2019: 27 · 2018: 25 · 2017: 24 · 2016: 32 · 2015: 7
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by-nc)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Danish Medical Research Council (1333-00120B)
- European Research Council (294666_DNAMET)
- Danish Cancer Society, Danish National Research Foundation (DNRF 82)
- Danish Council for Strategic Research
- Novo Nordisk Foundation
- Novo Nordisk Foundation Section for Stem Cell Biology in Human Disease
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- TET2, DNA hypermethylation, enhancer methylation, acute myeloid leukemia, AML1-ETO, leukemogenesis, hematopoietic cells, tumor suppressor, CpG islands, promoter methylation, DNA demethylation, leukemia mouse model, stem cell proliferation
- MeSH terms
- Animals, DNA-Binding Proteins, Enhancer Elements, Genetic, Hematopoietic Stem Cells, Humans, Mutation, Proto-Oncogene Proteins, Translocation, Genetic, Gene Expression Regulation, Neoplastic, DNA Methylation, Cell Proliferation, Dioxygenases, Mice, Carcinogenesis
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