Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice
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The Ten-Eleven-Translocation 2 (TET2) gene encodes a member of TET family enzymes that alters the epigenetic status of DNA by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Somatic loss-of-function mutations of TET2 are frequently observed in patients with diverse myeloid malignancies, including myelodysplastic syndromes, myeloproliferative neoplasms, and chronic myelomonocytic leukemia. By analyzing mice with targeted disruption of the Tet2 catalytic domain, we show here that Tet2 is a critical regulator of self-renewal and differentiation of hematopoietic stem cells (HSCs). Tet2 deficiency led to decreased genomic levels of 5hmC and augmented the size of the hematopoietic stem/progenitor cell pool in a cell-autonomous manner. In competitive transplantation assays, Tet2-deficient HSCs were capable of multilineage reconstitution and possessed a competitive advantage over wild-type HSCs, resulting in enhanced hematopoiesis into both lymphoid and myeloid lineages. In vitro, Tet2 deficiency delayed HSC differentiation and skewed development toward the monocyte/macrophage lineage. Our data indicate that Tet2 has a critical role in regulating the expansion and function of HSCs, presumably by controlling 5hmC levels at genes important for the self-renewal, proliferation, and differentiation of HSCs.
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Tet2 loss of function in murine HSPCs leads to increased self-renewal and pool expansion, higher competitive repopulation capacity, and a predisposition to hematological malignancy development.
“Indeed, Tet2 loss of function in murine HSPCs leads to increased self-renewal and pool expansion, higher competitive repopulation capacity, and a predisposition to hematological malignancy development.11, 12, 13”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [11]
In BM chimeras, Tet2+/− PB CD45.2+ cells show increased repopulating capacity compared with WT in the PBS groups.
“As previously reported, we observed increased repopulating capacity in Tet2+/− PB CD45.2+ compared with WT in the PBS groups.11, 12, 13”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [11]
Higher basal level of self-renewal, repopulation capacity, and general fitness is reported in Tet2 loss-of-function HSPCs.
“This likely results from a higher basal level of self-renewal, repopulation capacity, and general fitness reported in Tet2 loss-of-function HSPCs.11, 12, 13”
From Aging drives <i>Tet2</i> <i>+/−</i> clonal hematopoiesis via IL-1 signaling (2023) · cites this paper as [11]
Clonal haematopoiesis is a major risk factor for atherosclerotic disease.
“Clonal haematopoiesis does not just influence cancer development and therapeutic response but is also a major risk factor for atherosclerotic disease, which is another feature of ageing 87,88 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [87]
Mouse models carrying loss-of-function mutations in either TET2 or DNMT3A show an HSC competitive advantage in vivo as well as a propensity for leukemia when cooperating mutations are present.
“Mouse models carrying loss-of-function mutations in either of these genes clearly show an HSC competitive advantage in vivo as well as a propensity for leukemia when cooperating mutations are present 50–53.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [50]
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References 41 · Cited by 616
- Authors
- Ko, M., Bandukwala, H. S., An, J., Lamperti, E. D., Thompson, E. C., Hastie, R., Tsangaratou, A., Rajewsky, K., Koralov, S. B., & Rao, A.
- Affiliations
- La Jolla Institute for Immunology (US)
- Boston Children's Hospital (US)
- Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
- NYU Langone Health (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-08-22
- Volume
- 108
- Issue
- 35
- Pages
- 14566-14571
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3167529
- OpenAlex
- W1997998180
- Cited by
- 616
- References
- 41
- Citations by year
- 2026: 25 · 2025: 29 · 2024: 47 · 2023: 43 · 2022: 37 · 2021: 50 · 2020: 48 · 2019: 41 · 2018: 32 · 2017: 40 · 2016: 45 · 2015: 48 · 2014: 41 · 2013: 49 · 2012: 28
- FWCI
- 28.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- GlaxoSmithKline
- Lady Tata Memorial Trust
- Tata Trusts
- National Institutes of Health
- National Institute on Drug Abuse (RC1DA028422)
- National Cancer Institute (R01CA151535)
- National Institute of Allergy and Infectious Diseases (AI44432, R37AI054636, R01AI044432)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD065812, HD065812)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- TET2, hematopoietic stem cells, 5-hydroxymethylcytosine, DNA demethylation, hematopoietic stem cell self-renewal, hematopoietic stem cell differentiation, competitive transplantation, multilineage reconstitution, myeloid neoplasms, monocyte-to-macrophage differentiation, epigenetic regulation
- MeSH terms
- Animals, Cell Differentiation, DNA-Binding Proteins, Hematopoiesis, Hematopoietic Stem Cells, Homeostasis, Mice, Inbred C57BL, Proto-Oncogene Proteins, Dioxygenases, Mice
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