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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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Vitamin C epigenetically controls osteogenesis and bone mineralization
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Genetic and epigenetic determinants of AML pathogenesis
Cai, S. F., & Levine, R. L. (2018) · Seminars in Hematology · doi:10.1053/j.seminhematol.2018.08.001 · Cited by 117
“What primary prevention measures are indicated in this population, and at what point in time should clinicians intervene to mitigate the adverse sequelae associated with clonal hematopoiesis? For instance, 2 recent studies have demonstrated the reversibility of both stem cell dysfunction and leukemogenicity conferred…”
BackgroundLv, H., Zong, Q., Chen, C., Lv, G., Xiang, W., Xing, F., Jiang, G., Yan, B., Sun, X., Ma, Y., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-43743-9 · Cited by 117
“VC is known to exert anti-tumor activity through hydrogen peroxide-induced oxidative stress to preferentially kill cancer cells when used at high-doses or through control of TET enzymes activity to restore the abnormal DNA methylation pattern observed in many tumors 31,32 .”
Maternal vitamin C regulates reprogramming of DNA methylation and germline development
DiTroia, S. P., Percharde, M., Guerquin, M.-J., Wall, E. A., Collignon, É., Ebata, K. T., Mesh, K., Mahesula, S., Agathocleous, M., Laird, D. J., et al. (2019) · Nature · doi:10.1038/s41586-019-1536-1 · Cited by 117
Self-citationSystematic Review of Intravenous Ascorbate in Cancer Clinical Trials
Nauman, G., Gray, J. C., Parkinson, R., Levine, M., & Paller, C. J. (2018) · Antioxidants · doi:10.3390/antiox7070089 · Cited by 107
“Ascorbate action on TET may have promise in preventing tumor development especially in myelodysplastic syndrome [3,42].”
BackgroundIto, K., Lee, J., Chrysanthou, S., Zhao, Y., Josephs, K. S., Sato, H., Teruya‐Feldstein, J., Zheng, D., Dawlaty, M. M., & Ito, K. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.07.094 · Cited by 113
“Likewise, vitamin C (which boosts TET enzymatic activity) has been shown to be of therapeutic benefit in MDS and CMML disease in mice haploinsufficient for Tet2 (Agathocleous et al., 2017; Cimmino et al., 2017).”
BackgroundTulstrup, M., Soerensen, M., Hansen, J. W., Gillberg, L., Needhamsen, M., Kaastrup, K., Helin, K., Christensen, K., Weischenfeldt, J., & Grønbæk, K. (2021) · Nature Communications · doi:10.1038/s41467-021-26093-2 · Cited by 108
Vitamin C as a Modulator of the Response to Cancer Therapy
Błaszczak, W., Barczak, W., Masternak, J., Kopczyński, P., Zhitkovich, A., & Rubiś, B. (2019) · Molecules · doi:10.3390/molecules24030453 · Cited by 104
Large-scale targeted metabolomics method for metabolite profiling of human samples
Cao, G., Song, Z., Hong, Y., Yang, Z., Song, Y., Chen, Z., Chen, Z., & Cai, Z. (2020) · Analytica Chimica Acta · doi:10.1016/j.aca.2020.05.053 · Cited by 104
TET family dioxygenases and the TET activator vitamin C in immune responses and cancer
Yue, X., & Rao, A. (2020) · Blood · doi:10.1182/blood.2019004158 · Cited by 106
Epigenetic Regulation of Genomic Stability by Vitamin C
Brabson, J. P., Leesang, T. E., Mohammad, S., & Cimmino, L. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.675780 · Cited by 111
“Importantly, these effects could be reversed upon increased dietary vitamin C administration (Agathocleous et al., 2017).”
BackgroundInfluentialModest Declines in Proteome Quality Impair Hematopoietic Stem Cell Self-Renewal
Jose, L. H. S., Sunshine, M. J., Dillingham, C. H., Chua, B. A., Krutá, M., Hong, Y., Hatters, D. M., & Signer, R. A. J. (2020) · Cell Reports · doi:10.1016/j.celrep.2019.12.003 · Cited by 106
“Furthermore, glutathione levels do not significantly differ between HSCs and restricted progenitors (Agathocleous et al., 2017).”
Nuclear and Cytoplasmic Functions of Vitamin C
Zhitkovich, A. (2020) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.0c00348 · Cited by 106
Sun, J., He, X., Zhu, Y., Ding, Z., Dong, H., Feng, Y., Du, J., Wang, H., Wu, X., Zhang, L., et al. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.07.018 · Cited by 99
“Two recent reports demonstrate that vitamin C administration in vivo can activate TET2-related DNA demethylation and block leukemia progression (Agathocleous et al., 2017; Cimmino et al., 2017).”
Schönberger, K., Obier, N., Romero-Mulero, M. C., Cauchy, P., Mess, J., Pavlovich, P. V., Zhang, Y. W., Mitterer, M., Rettkowski, J., Lalioti, M., et al. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.10.002 · Cited by 97
Vitamin C – A new player in regulation of the cancer epigenome
Gillberg, L., Ørskov, A. D., Liu, M., Harsløf, L. B. S., Jones, P. A., & Grønbæk, K. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.11.001 · Cited by 100
Emerging Applications of Metabolomics in Clinical Pharmacology
Pang, H., Jia, W. P., & Hu, Z. (2019) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1538 · Cited by 95
Self-citationMetabolomic profiling of rare cell populations isolated by flow cytometry from tissues
DeVilbiss, A., Zhao, Z., Martin-Sandoval, M. S., Ubellacker, J. M., Tasdogan, A., Agathocleous, M., Mathews, T. P., & Morrison, S. J. (2021) · eLife · doi:10.7554/elife.61980 · Cited by 99
“All mass spectrometry data were acquired using a Thermo Scientific (Bremen, Germany) QExactive HF-X mass spectrometer (LC-MS/MS).”
BackgroundMethodInfluentialSelf-citationMeng, X., Pang, H., Sun, F., Jin, X., Wang, B., Yao, K., Yao, L., Wang, L., & Hu, Z. (2021) · Analytical Chemistry · doi:10.1021/acs.analchem.1c00767 · Cited by 96
Self-citationShenoy, N. K., Bhagat, T. D., Cheville, J. C., Lohse, C. M., Bhattacharyya, S., Tischer, A., Machha, V. R., Gordon-Mitchell, S., Choudhary, G. S., Wong, L.-F., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci98747 · Cited by 97
“AA is an essential cofactor for TET enzymes (binds to the catalytic domain and aids in conversion of Fe3+ to Fe2+ that is used by TET enzymes for conversion of methyl to hydroxymethyl cytosines) (Figure 4A) (13, 14).”
BackgroundVitamin B6 Addiction in Acute Myeloid Leukemia
Chen, C.-C., Li, B., Millman, S. E., Chen, C., Li, X., Morris, J. P., Mayle, A., Ho, Y.-J., Loizou, E., Liu, H., et al. (2020) · Cancer Cell · doi:10.1016/j.ccell.2019.12.002 · Cited by 95
“For example, vitamin C and D have recently been implicated in controlling a variety of cancer associated processes, and perturbations in these processes can modulate various cancer phenotypes (Agathocleous et al., 2017; Cimmino et al., 2017; Sherman et al., 2014; Yun et al., 2015).”
BackgroundMetabolomics, metabolic flux analysis and cancer pharmacology
Liang, L., Sun, F., Wang, H., & Hu, Z. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107827 · Cited by 99
Self-citationHematopoietic stem cell fate through metabolic control
Ito, K., & Ito, K. (2018) · Experimental Hematology · doi:10.1016/j.exphem.2018.05.005 · Cited by 98
Harnessing Hematopoietic Stem Cell Low Intracellular Calcium Improves Their Maintenance In Vitro
Luchsinger, L. L., Strikoudis, A., Danzl, N. M., Bush, E. C., Finlayson, M. O., Satwani, P., Sykes, M., Yazawa, M., & Snoeck, H. (2019) · Cell stem cell · doi:10.1016/j.stem.2019.05.002 · Cited by 100
“TET2 plays a major role in HSCs as Tet2−/− HSCs display extended replating in vitro, where they assume the phenotype of common myeloid progenitors, and show progressive myeloid bias in vivo that ultimately leads to myeloid malignancy (Agathocleous et al., 2017; Cimmino et al., 2017; Ko et al., 2011; Li et al., 2011; M…”
BackgroundCosgrove, J., Hustin, L., de Boer, R. J., & Perié, L. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.10.006 · Cited by 101
Mechanisms of anti-cancer effects of ascorbate: Cytotoxic activity and epigenetic modulation
Mastrangelo, D., Pelosi, E., Castelli, G., Lo‐Coco, F., & Testa, U. (2017) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2017.09.005 · Cited by 89
Deciphering the metabolic heterogeneity of hematopoietic stem cells with single-cell resolution
Cao, J., Yao, Q. J., Wu, J., Chen, X., Huang, L., Liu, W., Qian, K., Wan, J., & Zhou, B. O. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.12.005 · Cited by 87
Gillberg, L., Ørskov, A. D., Nasif, A., Ohtani, H., Madaj, Z., Hansen, J. W., Rapin, N., Mogensen, J. B., Liu, M., Dufva, I. H., et al. (2019) · Clinical Epigenetics · doi:10.1186/s13148-019-0739-5 · Cited by 91
“Dietary vitamin C was shown to compensate for Tet2 hetero- and homozygosity and postpone leukaemogenesis [19], whereas in vitamin C sufficient mice, pharmacological (high-dose intravenous) doses could compensate for the loss of Tet2 protein [20].”
BackgroundMetabolic regulation of somatic stem cells in vivo
Meacham, C. E., DeVilbiss, A. W., & Morrison, S. J. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00462-1 · Cited by 85
Self-citationClonal Hematopoiesis of Indeterminate Potential Reshapes Age-Related CVD
Khetarpal, S. A., Qamar, A., Bick, A. G., Fuster, J. J., Kathiresan, S., Jaiswal, S., & Natarajan, P. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.05.045 · Cited by 88
TLR9 and beclin 1 crosstalk regulates muscle AMPK activation in exercise
Liu, Y., Nguyen, P., Wang, X., Zhao, Y., Meacham, C. E., Zou, Z., Bordieanu, B., Johanns, M., Vertommen, D., Wijshake, T., et al. (2020) · Nature · doi:10.1038/s41586-020-1992-7 · Cited by 85
Self-citationEpigenetic Regulators as the Gatekeepers of Hematopoiesis
Rodrigues, C. P., Shvedunova, M., & Akhtar, A. (2020) · Trends in Genetics · doi:10.1016/j.tig.2020.09.015 · Cited by 99
Epigenetic Clock: DNA Methylation in Aging
Jiang, S., & Guo, Y. (2020) · Stem Cells International · doi:10.1155/2020/1047896 · Cited by 90
“Further evidence has revealed a direct connection between TET and HSC function in leukemogenesis [82].”
BackgroundYu, P., Wei, H., Zhong, P., Xue, Y., Wu, F., Liu, Y., Fei, J., & Mao, L. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202010195 · Cited by 81
Gene expression and risk of leukemic transformation in myelodysplasia
Shiozawa, Y., Malcovati, L., Gallì, A., Pellagatti, A., Karimi, M., Sato‐Otsubo, A., Sato, Y., Suzuki, H., Yoshizato, T., Yoshida, K., et al. (2017) · Blood · doi:10.1182/blood-2017-05-783050 · Cited by 82
Metabolic regulation of tissue stem cells
Shapira, S. N., & Christofk, H. R. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.04.004 · Cited by 82
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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