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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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ROS, Redox Regulation, and Anticancer Therapy
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Interplay between epigenetics and metabolism controls cancer stem cell plasticity
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“…MSCs for clinical use, we demonstrate that simultaneous treatment of MSCs in FBS-containing and de fi ned serum-free medium with an ATM activator, such as hydroxychloroquineorresveratrolandaTETactivator,suchasvitamin C 69 , inhibits replicative senescence and maintains early MSC properties.”
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“Ascorbate could activate αKGdependent dioxygenases to regulate cancer cell fate [30].”
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Epigenetic regulation of myogenesis by vitamin C
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“A similar epigenetic mode of action for VitC has recently been observed in bone cells (Thaler et al., 2022) and hematopoietic stem cells (Agathocleous et al., 2017; T. Zhang et al., 2019).”
InfluentialGuz, J., Zarakowska, E., Mijewski, P., Wasilow, A., Leśniewski, F., Foksiński, M., Brzoszczyk, B., Jarzemski, P., Gackowski, D., & Oliński, R. (2024) · Neoplasia · doi:10.1016/j.neo.2024.101079 · Cited by 7
Hematopoietic Stem Cell Intracellular Levels of Ca to the Rescue! What Next?
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A Bloody Feast—Nutritional Regulation of Hematopoiesis
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“In this regard, it is interesting to speculate that ascorbic acid supplementation, in addition to prevent disease progression in these Tet2deficient mouse models by phenocopying Tet2 functions (38,39), may be efficacious also for its well-known anti-inflammatory effects (40) (or vice versa, its anti-inflammatory effec…”
BackgroundXu, N., Yang, Y., Chen, L., Xu, L., Xu, X., & Lin, J. (2019) · Advanced Biosystems · doi:10.1002/adbi.201900006 · Cited by 7
Reilly, B. M., Luger, T., Park, S., Lio, C. J., González‐Avalos, E., Wheeler, E. C., Lee, M., Williamson, L. M., Tanaka, T. N., Diep, D. H., et al. (2020) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-20-0453 · Cited by 7
“To enhance the 5hmC signal in our clones, we took advantage of the fact that TET protein function can be enhanced by increased L-AA concentrations (47, 48).”
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“Notably, small molecules such as vitamins (folate, 10 ascorbic acid 11 ) and metabolic intermediates (eg, α -ke- toglutarate 12 ) can delay stem cell senescence by targeting key pathways like mTOR, AMPK, and NRF2.”
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The metabolic basis of inherited neutropenias
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“37 Leucine appears to be relatively enriched in normal maturing myeloid cells 9 and plays a role in metabolism including muscle atrophy and obesity.”
BackgroundSelf-citationHematopoietic Stem Cells as an Integrative Hub Linking Lifestyle to Cardiovascular Health
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“Notably, in this study, there is no obvious impact of voluntary running on HSC pool size, and HSC differentiation tendency is not investigated [152].”
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Visualizing metabolomics data with R
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Milbar, H. C., Caplan, A., Schwab, R. D., Coromilas, A. J., Baumrin, E., Forrestel, A., Steele, K. T., Micheletti, R. G., Perl, A., & Rosenbach, M. (2023) · Blood Advances · doi:10.1182/bloodadvances.2023009923 · Cited by 6
“21 Future studies measuring TET activity may reveal whether epigenetic dysregulation contributes to decreased Vc levels and elucidate possible mechanisms by which Vc supplementation may enhance antitumor immune responses or synergize with hypomethylating agents to improve outcomes in patients with AML.”
BackgroundInfluentialMolecular Studies for the Early Detection of Philadelphia-Negative Myeloproliferative Neoplasms
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“Interestingly, in this context, it was reported that vitamin C shows the ability to restores cellular sensitivity to imatinib, which can amplify the capacity of this BCR/ABL tyrosine kinase inhibitor (TKI) to promote a reduction in proliferation of the malignant cells [16].”
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Importance of Vitamin C in Human Health and Disease
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Novel therapies in myelodysplastic syndromes
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“Interestingly, in TET2-deficient mice and human cells, vitamin C has been shown to mimic TET2 function and restore hematopoiesis [54,55].”
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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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