The DOI matches its Crossref record; 58 of the 58 references it cites were found in a registry or an index.
Ascorbate regulates haematopoietic stem cell function and leukaemogenesis
Open accessAbstract
Stem-cell fate can be influenced by metabolite levels in culture, but it is not known whether physiological variations in metabolite levels in normal tissues regulate stem-cell function in vivo. Here we describe a metabolomics method for the analysis of rare cell populations isolated directly from tissues and use it to compare mouse haematopoietic stem cells (HSCs) to restricted haematopoietic progenitors. Each haematopoietic cell type had a distinct metabolic signature. Human and mouse HSCs had unusually high levels of ascorbate, which decreased with differentiation. Systemic ascorbate depletion in mice increased HSC frequency and function, in part by reducing the function of Tet2, a dioxygenase tumour suppressor. Ascorbate depletion cooperated with Flt3 internal tandem duplication (Flt3 ITD) leukaemic mutations to accelerate leukaemogenesis, through cell-autonomous and possibly non-cell-autonomous mechanisms, in a manner that was reversed by dietary ascorbate. Ascorbate acted cell-autonomously to negatively regulate HSC function and myelopoiesis through Tet2-dependent and Tet2-independent mechanisms. Ascorbate therefore accumulates within HSCs to promote Tet activity in vivo, limiting HSC frequency and suppressing leukaemogenesis.
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“ascorbate deficiency was shown to dysregulate HSC function in both a TET2-dependent and TET2-independent manner, leading to leukaemogenesis.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [72]
In the citing paper
“oral ascorbate may have a preventive role in leukaemogenesis72.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [72]
In the citing paper
“Using various GEMMs, including GULO-knockout mice, this study reveals that vitamin C is necessary for normal haematopoietic stem cell development and the prevention of leukaemia in mice.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [72]
In the citing paper
“Using various GEMMs, including GULO-knockout mice, this study reveals that vitamin C is necessary for normal haematopoietic stem cell development and the prevention of leukaemia in mice.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [72]
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Citations
Cites
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Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1
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“Tet enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), then catalyze some steps toward unmethylated cytosine 24,25 .”
Age-related clonal hematopoiesis associated with adverse outcomes
Jaiswal, S., Fontanillas, P., Flannick, J., Manning, A., Grauman, P. V., Mar, B. G., Lindsley, R. C., Mermel, C. H., Burtt, N., Chavez, A., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1408617 · Cited by 4,841 · cited 1×
“Moreover, clonal hematopoiesis of indeterminate potential is common among older humans and is often associated with loss of one Tet2 allele 45–47 .”
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Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine
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“Tet enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), then catalyze some steps toward unmethylated cytosine 24,25 .”
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“Metabolomics data analysis and hierarchical clustering were performed using MetaboAnalyst 54 and Simca (Umetrics).”
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“TET2 mutations cooperate with FLT3 ITD mutations to cause acute myeloid leukaemia (AMLs) 31,35 .”
Mutation in TET2 in Myeloid Cancers
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“Tet2 inactivating mutations are early events in leukaemogenesis 26 that increase HSC frequency and self-renewal 27–29 and cause leukaemia when combined with other mutations 30–32 .”
Inducible Gene Targeting in Mice
Kühn, R., Schwenk, F., Aguet, M., & Rajewsky, K. (1995) · Science · doi:10.1126/science.7660125 · Cited by 1,641
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 · cited 3×
“Consistent with prior studies 27–29 , conditional deletion of Tet2 in adult haematopoietic cells significantly increased HSC frequency and function (Extended Data Fig.”
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“Additionally, vitamin C can negatively regulate hematopoietic stem cell (HSC) function by promoting the activity of Tet2 [96].”
BackgroundThe impact of cellular metabolism on chromatin dynamics and epigenetics
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Metadata
- Authors
- Agathocleous, M., Meacham, C. E., Burgess, R. J., Piskounova, E., Zhao, Z., Crane, G. M., Cowin, B. L., Bruner, E., Murphy, M. M., Chen, W., Spangrude, G. J., Hu, Z., DeBerardinis, R. J., & Morrison, S. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of Utah (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Morrison, Sean J.
- ORCID
- Venue
- Nature
- Published
- 2017-08-21
- Volume
- 549
- Issue
- 7673
- Pages
- 476-481
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5910063
- OpenAlex
- W2746373891
- Cited by
- 545
- References
- 58
- Citations by year
- 2026: 30 · 2025: 52 · 2024: 62 · 2023: 73 · 2022: 53 · 2021: 71 · 2020: 91 · 2019: 45 · 2018: 51 · 2017: 17
- FWCI
- 42.84
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute on Aging (R37AG024945)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100848)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- vitamin C, hematopoietic stem cells, leukemogenesis, TET2, dioxygenase, FLT3-ITD, hematopoietic progenitor cells, cellular metabolism, stem cell differentiation, myelopoiesis, tumour suppressor
- MeSH terms
- Animals, Ascorbic Acid, Ascorbic Acid Deficiency, DNA-Binding Proteins, Female, Hematopoietic Stem Cells, Humans, Leukemia, Male, Proto-Oncogene Proteins, Myelopoiesis, Dioxygenases, Mice, fms-Like Tyrosine Kinase 3, Metabolomics, Carcinogenesis
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