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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]
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“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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Citations
Cites
Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia
The Cancer Genome Atlas Research Network (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1301689 · Cited by 5,078
A decade of exploring the cancer epigenome—biological and translational implications
Baylin, S. B., & Jones, P. A. (2011) · Nature Reviews Cancer · doi:10.1038/nrc3130 · Cited by 2,871
Figueroa, M. E., Abdel-Wahab, O., Lu, C., Ward, P. S., Patel, J., Shih, A., Li, Y., Bhagwat, N., Vasanthakumar, A., Fernandez, H. F., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.11.015 · Cited by 2,766
The accessible chromatin landscape of the human genome
Thurman, R. E., Rynes, E., Humbert, R., Vierstra, J., Maurano, M. T., Haugen, E., Sheffield, N. C., Stergachis, A. B., Wang, H., Vernot, B., et al. (2012) · Nature · doi:10.1038/nature11232 · Cited by 2,679
An atlas of active enhancers across human cell types and tissues
The FANTOM Consortium, Andersson, R., Gebhard, C., Miguel-Escalada, I., Hoof, I., Bornholdt, J., Boyd, M., Chen, Y., Zhao, X., Schmidl, C., et al. (2014) · Nature · doi:10.1038/nature12787 · Cited by 2,550
Self-citationGenome-scale DNA methylation maps of pluripotent and differentiated cells
Meissner, A., Mikkelsen, T. S., Gu, H., Wernig, M., Hanna, J., Sivachenko, A., Zhang, X., Bernstein, B. E., Nusbaum, C., Jaffe, D. B., et al. (2008) · Nature · doi:10.1038/nature07107 · Cited by 2,536
Function and information content of DNA methylation
Schübeler, D. (2015) · Nature · doi:10.1038/nature14192 · Cited by 2,060
Mutation in TET2 in Myeloid Cancers
Delhommeau, F., Dupont, S., Valle, V. D., James, C., Trannoy, S., Massé, A., Kosmider, O., Le Couedic, J.-P., Robert, F., Alberdi, A., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810069 · Cited by 1,776
Self-citationDNA-binding factors shape the mouse methylome at distal regulatory regions
Stadler, M. B., Murr, R., Burger, L., Ivanek, R., Lienert, F., Schöler, A., Nimwegen, E. V., Wirbelauer, C., Oakeley, E. J., Gaidatzis, D., et al. (2011) · Nature · doi:10.1038/nature10716 · Cited by 1,383
Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2
Ko, M., Huang, Y., Jankowska, A. M., Pape, U. J., Tahiliani, M., Bandukwala, H. S., An, J., Lamperti, E. D., Koh, K. P., Ganetzky, R. D., et al. (2010) · Nature · doi:10.1038/nature09586 · Cited by 1,340
Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation
Moran-Crusio, K., Reavie, L., Shih, A., Abdel-Wahab, O., Ndiaye-Lobry, D., Lobry, C., Figueroa, M. E., Vasanthakumar, A., Patel, J., Zhao, X., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.06.001 · Cited by 1,339
Base-Resolution Analysis of 5-Hydroxymethylcytosine in the Mammalian Genome
Yu, M., Hon, G. C., Szulwach, K. E., Song, C., Zhang, L., Kim, A., Li, X., Dai, Q., Shen, Y., Park, B., et al. (2012) · Cell · doi:10.1016/j.cell.2012.04.027 · Cited by 1,050
TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity
Williams, K., Christensen, J., Pedersen, M. T., Johansen, J. V., Cloos, P. A. C., Rappsilber, J., & Helin, K. (2011) · Nature · doi:10.1038/nature10066 · Cited by 1,021
Self-citationQuivoron, C., Couronné, L., Della Valle, V., Lopez, C. K., Plo, I., Wagner-Ballon, O., Do Cruzeiro, M., Delhommeau, F., Arnulf, B., Stern, M.-H., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.06.003 · Cited by 924
Self-citationTETonic shift: biological roles of TET proteins in DNA demethylation and transcription
Pastor, W. A., Aravind, L., & Rao, A. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3589 · Cited by 897 · cited 4×
“In accordance, cooperation of Tet2 deficiency with KIT activation (Soucie et al. 2012; Pastor et al. 2013) and with inactivation of the Notch pathway (Lobry et al. 2013; Solary et al. 2014) was recently demonstrated.”
BackgroundInfluentialRecurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis
Busque, L., Patel, J. P., Figueroa, M. E., Vasanthakumar, A., Provost, S., Hamilou, Z., Mollica, L., Li, J., Viale, A., Heguy, A., et al. (2012) · Nature Genetics · doi:10.1038/ng.2413 · Cited by 830
Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells
Pastor, W. A., Pape, U. J., Huang, Y., Henderson, H. R., Lister, R., Ko, M., McLoughlin, E. M., Brudno, Y., Mahapatra, S., Kapranov, P., et al. (2011) · Nature · doi:10.1038/nature10102 · Cited by 804
DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryosPreprint
Messerschmidt, D. M., Knowles, B. B., & Solter, D. (2014) · Genes & Development · doi:10.1101/gad.234294.113 · Cited by 762
Acquired mutations in TET2 are common in myelodysplastic syndromes
Langemeijer, S. M. C., Kuiper, R. P., Berends, M., Knops, R., Aslanyan, M. G., Massop, M., Stevens-Linders, E., van Hoogen, P., van Kessel, A. G., Raymakers, R. A. P., et al. (2009) · Nature Genetics · doi:10.1038/ng.391 · Cited by 755
Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia
Jan, M., Snyder, T. M., Corces-Zimmerman, M. R., Vyas, P., Weissman, I. L., Quake, S. R., & Majeti, R. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004315 · Cited by 721
The role of mutations in epigenetic regulators in myeloid malignancies
Shih, A. H., Abdel-Wahab, O. I., Patel, J. P., & Levine, R. L. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3343 · Cited by 696
Li, Z., Cai, X., Cai, C.-L., Wang, J., Zhang, W., Petersen, B. E., Yang, F.-C., & Xu, M. (2011) · Blood · doi:10.1182/blood-2010-12-325241 · Cited by 671
Haferlach, T., Kohlmann, A., Wieczorek, L., Basso, G., Kronnie, G. T., Béné, M. C., Vos, J. D., Hernández‐Rivas, J. M., Hofmann, W., Mills, K., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.23.4732 · Cited by 667
Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia
Somervaille, T. C. P., & Cleary, M. L. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.08.020 · Cited by 582
Tsumura, A., Hayakawa, T., Kumaki, Y., Takebayashi, S., Sakaue, M., Matsuoka, C., Shimotohno, K., Ishikawa, F., Li, E., Ueda, H. R., et al. (2006) · Genes to Cells · doi:10.1111/j.1365-2443.2006.00984.x · Cited by 558
5-Hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells
Stroud, H., Feng, S., Kinney, S. R. M., Pradhan, S., & Jacobsen, S. E. (2011) · Genome biology · doi:10.1186/gb-2011-12-6-r54 · Cited by 490
Aging and epigenetic drift: a vicious cycle
Issa, J.-P. (2014) · Journal of Clinical Investigation · doi:10.1172/jci69735 · Cited by 419
Hon, G. C., Song, C., Du, T., Jin, F., Selvaraj, S., Lee, A. Y., Yen, C., Ye, Z., Mao, S.-Q., Wang, B.-A., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.08.026 · Cited by 349
DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes
Aran, D., Sivan Sabato, A., & Hellman, A. (2013) · Genome biology · doi:10.1186/gb-2013-14-3-r21 · Cited by 342
Extensive Variation in Chromatin States Across Humans
Kasowski, M., Kyriazopoulou-Panagiotopoulou, S., Grubert, F., Zaugg, J. B., Kundaje, A., Liu, Y., Boyle, A. P., Zhang, Q. C., Zakharia, F., Spacek, D. V., et al. (2013) · Science · doi:10.1126/science.1242510 · Cited by 339
Age-associated epigenetic drift: implications, and a case of epigenetic thrift?
Teschendorff, A. E., West, J., & Beck, S. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt375 · Cited by 330
Landan, G., Cohen, N. M., Mukamel, Z., Bar, A., Molchadsky, A., Brosh, R., Horn-Saban, S., Zalcenstein, D. A., Goldfinger, N., Zundelevich, A., et al. (2012) · Nature Genetics · doi:10.1038/ng.2442 · Cited by 305
The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases
Solary, É., Bernard, O., Tefferi, A., Fuks, F., & Vainchenker, W. (2013) · Leukemia · doi:10.1038/leu.2013.337 · Cited by 298
Self-citationAkalin, A., Garrett-Bakelman, F. E., Kormaksson, M., Busuttil, J., Zhang, L., Khrebtukova, I., Milne, T. A., Huang, Y., Biswas, D., Hess, J. L., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002781 · Cited by 296
Clonal architecture of chronic myelomonocytic leukemias
Itzykson, R., Kosmider, O., Renneville, A., Morabito, M., Preudhomme, C., Berthon, C., Adès, L., Fenaux, P., Platzbecker, U., Gagey, O., et al. (2013) · Blood · doi:10.1182/blood-2012-06-440347 · Cited by 291
Self-citationYan, M., Kanbe, E., Peterson, L. F., Boyapati, A., Miao, Y., Wang, Y., Chen, I.-M., Chen, Z., Rowley, J. D., Willman, C. L., et al. (2006) · Nature Medicine · doi:10.1038/nm1443 · Cited by 279
Role of Tet proteins in enhancer activity and telomere elongationPreprint
Lu, F., Liu, Y., Jiang, L., Yamaguchi, S., & Zhang, Y. (2014) · Genes & Development · doi:10.1101/gad.248005.114 · Cited by 278
Landscape of TET2 mutations in acute myeloid leukemia
Weißmann, S., Alpermann, T., Grossmann, V., Kowarsch, A., Nadarajah, N., Eder, C., Dicker, F., Fasan, A., Haferlach, C., Haferlach, T., et al. (2011) · Leukemia · doi:10.1038/leu.2011.326 · Cited by 272
Enhancer Function: Mechanistic and Genome-Wide Insights Come Together
Plank, J. L., & Dean, A. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.06.015 · Cited by 263
TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia
Kosmider, O., Gelsi‐Boyer, V., Ciudad, M., Racoeur, C., Jooste, V., Vey, N., Quesnel, B., Fenaux, P., Bastie, J.-N., Beyne‐Rauzy, O., et al. (2009) · Haematologica · doi:10.3324/haematol.2009.011205 · Cited by 255
Self-citationDNA methylation status predicts cell type‐specific enhancer activity
Wiench, M., John, S., Baek, S., Johnson, T. A., Sung, M., Escobar, T., Simmons, C. A., Pearce, K. H., Biddie, S. C., Sabo, P. J., et al. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.210 · Cited by 245
Ptasinska, A., Assi, S. A., Mannari, D., James, S. R., Williamson, D., Dunne, J., Hoogenkamp, M., Wu, M., Care, M., McNeill, H., et al. (2012) · Leukemia · doi:10.1038/leu.2012.49 · Cited by 184
Notch pathway activation targets AML-initiating cell homeostasis and differentiation
Lobry, C., Ntziachristos, P., Ndiaye‐Lobry, D., Oh, P., Cimmino, L., Zhu, N., Araldi, E., Hu, W., Freund, J. E., Abdel-Wahab, O. I., et al. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20121484 · Cited by 169
Asmar, F., Punj, V., Christensen, J. F., Pedersen, M. T., Pedersen, A., Nielsen, A. B., Hother, C. E., Ralfkiær, U., Brown, P. D. N., Ralfkiaer, E. M., et al. (2013) · Haematologica · doi:10.3324/haematol.2013.088740 · Cited by 147
Self-citationWu, H., & Zhang, Y. (2011) · Cell Cycle · doi:10.4161/cc.10.15.16930 · Cited by 132
Origins of aberrant DNA methylation in acute myeloid leukemia
Schoofs, T., Berdel, W. E., & Müller‐Tidow, C. (2013) · Leukemia · doi:10.1038/leu.2013.242 · Cited by 127
Effects ofTET2mutations on DNA methylation in chronic myelomonocytic leukemia
Yamazaki, J., Taby, R. F., Vasanthakumar, A., Macrae, T. A., Ostler, K. R., Shen, L., Kantarjian, H. M., Estecio, M. R., Jelı́nek, J., Godley, L. A., et al. (2012) · Epigenetics · doi:10.4161/epi.7.2.19015 · Cited by 125
In aggressive forms of mastocytosis, TET2 loss cooperates with c-KITD816V to transform mast cells
Soucie, E. L., Hanssens, K., Mercher, T., Georgin‐Lavialle, S., Damaj, G. L., Livideanu, C. B., Chandesris, M., Acin, Y., Letard, S., Sepulveda, P. D., et al. (2012) · Blood · doi:10.1182/blood-2011-12-397588 · Cited by 108
Self-citationMartens, J. H. A., Mandoli, A., Simmer, F., Wierenga, B., Saeed, S., Singh, A. A., Altucci, L., Vellenga, E., & Stunnenberg, H. G. (2012) · Blood · doi:10.1182/blood-2012-05-429050 · Cited by 102
TET2 is essential for survival and hematopoietic stem cell homeostasis
Shide, K., Kameda, T., Shimoda, H. K., Yamaji, T., Abe, H., Kamiunten, A., Sekine, M., Hidaka, T., Katayose, K., Kubuki, Y., et al. (2012) · Leukemia · doi:10.1038/leu.2012.94 · Cited by 90
Age-related epigenetic drift in the pathogenesis of MDS and AMLPreprint
Maegawa, S., Gough, S. M., Watanabe‐Okochi, N., Lu, Y., Zhang, N., Castoro, R. J., Estecio, M. R., Jelı́nek, J., Liang, S., Kitamura, T., et al. (2014) · Genome Research · doi:10.1101/gr.157529.113 · Cited by 83
Pérez, C., Martínez‐Calle, N., Martín-Subero, J. I., Segura, V., Delabesse, É., Fernández‐Mercado, M., Gárate, L., Álvarez, S., Rifón, J., Varea, S., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031605 · Cited by 78
Lo, M., Peterson, L. F., Yan, M., Cong, X., Jin, F., Shia, W.-J., Matsuura, S., Ahn, E.-Y. E., Komeno, Y., Ly, M., et al. (2012) · Blood · doi:10.1182/blood-2011-12-395335 · Cited by 33
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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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