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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
IDH1 and IDH2 Mutations in Gliomas
Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808710 · Cited by 5,847
Conversion of 5-Methylcytosine to 5-Hydroxymethylcytosine in Mammalian DNA by MLL Partner TET1
Tahiliani, M., Koh, K. P., Shen, Y., Pastor, W. A., Bandukwala, H., Brudno, Y., Agarwal, S., Iyer, L. M., Liu, D. R., Aravind, L., et al. (2009) · Science · doi:10.1126/science.1170116 · Cited by 5,836 · cited 1×
“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 .”
Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence
Genovese, G., Kähler, A. K., Handsaker, R. E., Lindberg, J., Rose, S. A., Bakhoum, S. F., Chambert, K., Mick, E., Neale, B. M., Fromer, M., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1409405 · Cited by 3,531
Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine
Ito, S., Shen, L., Dai, Q., Wu, S. C., Collins, L. B., Swenberg, J. A., He, C., & Zhang, Y. (2011) · Science · doi:10.1126/science.1210597 · Cited by 3,451 · cited 1×
“Tet enzymes convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), then catalyze some steps toward unmethylated cytosine 24,25 .”
MetaboAnalyst 3.0—making metabolomics more meaningful
Xia, J., Sinelnikov, I. V., Han, B., & Wishart, D. S. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv380 · Cited by 2,680 · cited 1×
“Metabolomics data analysis and hierarchical clustering were performed using MetaboAnalyst 54 and Simca (Umetrics).”
Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia
Patel, J. P., Gönen, M., Figueroa, M. E., Fernandez, H. F., Sun, Z., Racevskis, J., Vlierberghe, P. V., Dolgalev, I., Thomas, S., Aminova, O., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1112304 · Cited by 1,990 · cited 1×
“TET2 mutations cooperate with FLT3 ITD mutations to cause acute myeloid leukaemia (AMLs) 31,35 .”
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 · cited 1×
“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.”
Flagged first, then by citations
Cited by
Sorted by citations
Items 101–200 of 555
Metabolism as master of hematopoietic stem cell fate
Ito, K., Bonora, M., & Ito, K. (2018) · International Journal of Hematology · doi:10.1007/s12185-018-2534-z · Cited by 85
“For example, vitamin C has been found to mimic Tet2 restoration in Tet2-knockdown HSCs by promoting DNA demethylation and reversing aberrant self-renewal, thereby altering the progression of leukemia [80, 112].”
Atherosclerosis in diabetes mellitus: novel mechanisms and mechanism-based therapeutic approaches
Khan, A. W., & Jandeleit-Dahm, K. A. M. (2025) · Nature Reviews Cardiology · doi:10.1038/s41569-024-01115-w · Cited by 93
“Some approaches targeting TET2 activity have shown promising results in preclinical studies 105,106 .”
Clonal hematopoiesis and inflammation – the perpetual cycle
Avagyan, S., & Zon, L. I. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.12.001 · Cited by 79
Aspartate availability limits hematopoietic stem cell function during hematopoietic regeneration
Qi, L., Martin-Sandoval, M. S., Merchant, S., Gu, W., Eckhardt, M., Mathews, T. P., Zhao, Z., Agathocleous, M., & Morrison, S. J. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.07.011 · Cited by 85
Self-citationVitamin C increases 5-hydroxymethylcytosine level and inhibits the growth of bladder cancer
Ding, P., Ge, G., Gong, Y., Zhan, Y., He, S., Guan, B., Li, Y., Xu, Z., Hao, H., He, Z., et al. (2018) · Clinical Epigenetics · doi:10.1186/s13148-018-0527-7 · Cited by 78
Jiang, L., Ye, Y., Han, Y., Wang, Q., Lu, H., Li, J., Qian, W., Zeng, X. Y., Zhang, Z., Zhao, Y., et al. (2024) · Cell Discovery · doi:10.1038/s41421-024-00665-0 · Cited by 87
Metabolic determinants of tumour initiation
Brunner, J. S., & Finley, L. W. S. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00773-5 · Cited by 78
Ferrone, C. K., Blydt-Hansen, M., & Rauh, M. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21020626 · Cited by 80
“Similarly, Agathocleous et al. (2017) demonstrated that ascorbate (vitamin C) regulates TET2 function in hematopoietic stem cells (HSCs).”
BackgroundElectrochemically Probing Dynamics of Ascorbate during Cytotoxic Edema in Living Rat Brain
Jin, J., Ji, W., Li, L., Zhao, G., Wu, W., Wei, H., Ma, F., Jiang, Y. Y., & Mao, L. (2020) · Journal of the American Chemical Society · doi:10.1021/jacs.0c09011 · Cited by 72
TET2 as a tumor suppressor and therapeutic target in T-cell acute lymphoblastic leukemia
Bensberg, M., Rundquist, O., Selimović-Pašić, A., Lagerwall, C., Benson, M., Gustafsson, M., Vogt, H., Lentini, A., & Nestor, C. E. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2110758118 · Cited by 70
“Similarly, vitamin C was shown to maintain normal Tet2 activity in HSCs in vivo, thereby decreasing HSC turnover and malignant transformation (17).”
BackgroundDifferentiation therapy of myeloid leukemia: four decades of development
Madan, V., & Koeffler, H. P. (2020) · Haematologica · doi:10.3324/haematol.2020.262121 · Cited by 72
Smirnoff, N., & Wheeler, G. L. (2024) · Journal of Experimental Botany · doi:10.1093/jxb/erad505 · Cited by 70
DNA methylation processes in atherosclerotic plaque
Aavik, E., Babu, M., & Ylä‐Herttuala, S. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.12.006 · Cited by 72
Castelli, G., Logozzi, M., Mizzoni, D., Raimo, R. D., Cerio, A., Dolo, V., Pasquini, L., Screnci, M., Ottone, T., Testa, U., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242115663 · Cited by 69
“Particularly, it has been shown that there is a clear relationship between the activity of TET enzymes, vitamin C and the development of hematopoietic malignancies [7,8].”
BackgroundFuloria, S., Subramaniyan, V., Sundram, K., Kumari, U., Sathasivam, K. V., Meenakshi, D. U., Wu, Y. S., Sekar, M., Chitranshi, N., Malviya, R., et al. (2021) · Antioxidants · doi:10.3390/antiox10010128 · Cited by 77
“translocation-2 (TET2) activity [168]; and NAC is reported to produce hydrogen sulfide”
BackgroundMetabolic Regulation of Hematopoietic Stem Cells
Morganti, C., Cabezas‐Wallscheid, N., & Ito, K. (2022) · HemaSphere · doi:10.1097/hs9.0000000000000740 · Cited by 82
Radivoyevitch, T., Dean, R. M., Shaw, B. E., Brazauskas, R., Tecca, H. R., Molenaar, R. J., Battiwalla, M., Savani, B. N., Flowers, M. E. D., Cooke, K. R., et al. (2018) · Leukemia Research · doi:10.1016/j.leukres.2018.07.016 · Cited by 68
Sub-nanoliter metabolomics via mass spectrometry to characterize volume-limited samples
Li, Y., Bouza, M., Wu, C., Guo, H., Huang, D., Doron, G., Temenoff, J. S., Stecenko, A. A., Wang, Z. L., & Fernández, F. M. (2020) · Nature Communications · doi:10.1038/s41467-020-19444-y · Cited by 67
Mass spectrometry‐based strategies for single‐cell metabolomics
Hu, R., Li, Y., Yang, Y., & Liu, M. (2021) · Mass Spectrometry Reviews · doi:10.1002/mas.21704 · Cited by 65
Lu, Y., Wu, Q.-N., Chen, D.-L., Chen, L.-Z., Wang, Z., Ren, C., Mo, H., Ya, C., Sheng, H., Wang, Y.-N., et al. (2018) · Theranostics · doi:10.7150/thno.21745 · Cited by 67
“Ascorbate was reported to enhance regeneration of induced pluripotent stem cells and inhibit malignant progression of leukemia via modulation of DNA demethylation dioxygenases[14, 15, 34].”
BackgroundClonal hematopoiesis in cancer
Park, S. J., & Bejar, R. L. (2020) · Experimental Hematology · doi:10.1016/j.exphem.2020.02.001 · Cited by 66
Qi, T., Sun, M., Zhang, C., Chen, P., Xiao, C., & Chang, X. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108452 · Cited by 63
Guan, Y., Tiwari, A. D., Phillips, J. G., Hasipek, M., Grabowski, D., Pagliuca, S., Gopal, P., Kerr, C. M., Ademà, V., Radivoyevitch, T., et al. (2020) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-20-0173 · Cited by 64
“To date, the only TET2MTtargeted therapeutic compound aimed at restoration of TET2 activity is vitamin C, a cofactor in TET2 catalysis (12, 13).”
BackgroundTET-Mediated Epigenetic Regulation in Immune Cell Development and Disease
Tsiouplis, N. J., Bailey, D. W., Chiou, L. F., Wissink, F. J., & Tsagaratou, A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.623948 · Cited by 63
Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells
Dellorusso, P. V., Proven, M. A., Calero‐Nieto, F. J., Wang, X., Mitchell, C. A., Hartmann, F. J., Amouzgar, M., Favaro, P. M. B., DeVilbiss, A., Swann, J. W., et al. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.04.020 · Cited by 66
Self-citationChen, C., Hao, X., Lai, X., Liu, L., Zhu, J., Shao, H., Huang, D., Gu, H., Zhang, T., Yu, Z., et al. (2021) · Science Advances · doi:10.1126/sciadv.abd6280 · Cited by 63
The role of vitamin C in epigenetic cancer therapy
Mikkelsen, S. U., Gillberg, L., Lykkesfeldt, J., & Grønbæk, K. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.03.017 · Cited by 62
Li, X., Wu, C., Shen, Y., Wang, K., Tang, L., Zhou, M., Yang, M., Pan, T., Liu, X., & Xu, W. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001265 · Cited by 61
“A recent study shows that vitamin C is therapeutically effective for treating TET2-deficient leukemia by regulating stem cell proliferation (36, 37), indicating that vitamin C could also be potentially important for PE.”
BackgroundEpigenetic Gene Regulation by Dietary Compounds in Cancer Prevention
Montgomery, M. R., & Srinivasan, A. (2019) · Advances in Nutrition · doi:10.1093/advances/nmz046 · Cited by 66
“New evidence also suggests that vitamin C may help regulate hematopoietic stem cell function and protect against leukemia progression via DNA demethylation (208, 209).”
BackgroundThe Clinical Management of Clonal Hematopoiesis
Bolton, K. L., Zehir, A., Ptashkin, R. N., Patel, M. A., Gupta, D., Sidlow, R., Papaemmanuil, E., Berger, M. F., & Levine, R. L. (2020) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2019.11.006 · Cited by 60
The Bidirectional Relationship Between Cancer Epigenetics and Metabolism
Izzo, L., Affronti, H. C., & Wellen, K. E. (2020) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-070820-035832 · Cited by 64
“Additionally, ascorbate is a cofactor of 2-oxoglutarate-dependent dioxygenases, and its supplementation promotes TET enzyme activity to exert anticancer effects (Agathocleous et al. 2017; Cimmino et al. 2017; Shenoy et al. 2017, 2019; Mingay et al. 2018; Mustafi et al. 2018).”
BackgroundGonzález‐Menéndez, P., Romano, M., Yan, H., Deshmukh, R. S., Papoin, J., Oburoglu, L., Daumur, M., Dumé, A., Phadke, I., Mongellaz, C., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108723 · Cited by 60
“Indeed, recent studies have shown that ascorbate is able to compensate for TET2 deficiency and suppress leukemogenesis, albeit via both TET2dependent and TET2-independent mechanisms (Agathocleous et al., 2017; Cimmino et al., 2017).”
BackgroundD’Aniello, C., Cermola, F., Palamidessi, A., Wanderlingh, L. G., Gagliardi, M., Migliaccio, A., Varrone, F., Casalino, L., Matarazzo, M. R., Cesare, D. D., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-2070 · Cited by 60
“VitC, for 15 instance, by enhancing the activity of the TET and JMJ demethylases, improves the efficiency of 16 induced pluripotent stem cell (iPSC) generation (7-10), drives embryonic stem cells (ESCs) 17 towards a naive state of pluripotency (11, 12) and regulates the balance between self-renewal and 18 differentiat…”
BackgroundEstablishing mechanisms affecting the individual response to ionizing radiation
Averbeck, D., Candéias, S. M., Chandna, S., Foray, N., Friedl, A. A., Haghdoost, S., Jeggo, P. A., Lumniczky, K., Paris, F., Quintens, R., et al. (2019) · International Journal of Radiation Biology · doi:10.1080/09553002.2019.1704908 · Cited by 69
“Vitamin C is an important modulator of the activity of the methylcytosine dioxygenase TET2, which is involved in DNA regulating methylation status (Agathocleous et al. 2017; Cimmino et al. 2017).”
BackgroundThe requirement for pyruvate dehydrogenase in leukemogenesis depends on cell lineage
Jun, S., Mahesula, S., Mathews, T. P., Martin-Sandoval, M. S., Zhao, Z., Piskounova, E., & Agathocleous, M. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.07.016 · Cited by 58
Self-citationBoucai, L., Falcone, J., Ukena, J., Coombs, C. C., Zehir, A., Ptashkin, R. N., Berger, M. F., Levine, R. L., & Fagin, J. A. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-00803 · Cited by 57
“colony formation and leukemia progression (34, 35).”
Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis
Jeong, J. J., Gu, X., Nie, J., Sundaravel, S., Liu, H., Kuo, W.-L., Bhagat, T. D., Pradhan, K., Cao, J. Z., Nischal, S., et al. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1138 · Cited by 64
“TET enzymes require cofactors/substrates such as iron, oxygen and alpha-ketoglutarate for their catalytic activity, and also ascorbate, which indirectly increase TET activity by acting on iron oxidation state leading to modulation of hydroxymethylcytosine levels in various models (1, 6, 7).”
BackgroundTET2: A cornerstone in normal and malignant hematopoiesis
Kunimoto, H., & Nakajima, H. (2020) · Cancer Science · doi:10.1111/cas.14688 · Cited by 56
Mitochondria and Hypoxia: Metabolic Crosstalk in Cell-Fate Decisions
Bargiela, D., Burr, S. P., & Chinnery, P. F. (2018) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2018.02.002 · Cited by 60
Calcium regulation of stem cells
Snoeck, H. (2020) · EMBO Reports · doi:10.15252/embr.202050028 · Cited by 59
“Tet2 (cid:1) / (cid:1) HSCs show progressive myeloid bias in vivo that ultimately leads to myeloid malignancy [136 – 141].”
Talib, W. H., Jum'Ah, D., Attallah, Z. S., Jallad, M. S., Kury, L. T. A., Hadi, R. W., & Mahmod, A. I. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1281879 · Cited by 64
Nakauchi, Y., Azizi, A., Thomas, D., Corces, M. R., Reinisch, A., Sharma, R., Hernandez, D. C., Köhnke, T., Karigane, D., Fan, A. C., et al. (2022) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-21-0143 · Cited by 60
Context dependent effects of ascorbic acid treatment in TET2 mutant myeloid neoplasia
Guan, Y., Greenberg, E. F., Hasipek, M., Shi, C., Liu, X., Kerr, C. M., Gackowski, D., Zarakowska, E., Radivoyevitch, T., Gu, X., et al. (2020) · Communications Biology · doi:10.1038/s42003-020-01220-9 · Cited by 59
The Epigenetic Role of Vitamin C in Neurodevelopment
Coker, S. J., Smith-Díaz, C. C., Dyson, R. M., Vissers, M. C. M., & Berry, M. J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031208 · Cited by 57
Inflammation-induced epigenetic imprinting regulates intestinal stem cells
Zhao, D., Ravikumar, V., Leach, T. J., Kraushaar, D. C., Lauder, E., Li, L., Sun, Y., Oravecz-Wilson, K. I., Keller, E. T., Chen, F., et al. (2024) · Cell stem cell · doi:10.1016/j.stem.2024.08.006 · Cited by 58
He, X., Wang, Q., Cheng, X., Wang, W., Li, Y., Nan, Y., Wu, J., Xiu, B., Jiang, T., Bergholz, J. S., et al. (2025) · Cell · doi:10.1016/j.cell.2025.01.043 · Cited by 57
Diabetes-Driven Atherosclerosis: Updated Mechanistic Insights and Novel Therapeutic Strategies
Karakasis, P., Theofilis, P., Patoulias, D., Vlachakis, P. K., Antoniadis, A. P., & Fragakis, N. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26052196 · Cited by 63
“Preclinical studies have shown promise in targeting CHIP and TET2-related pathways [105,106].”
Das, A. B., Kakadia, P. M., Wojcik, D. P., Pemberton, L. C., Browett, P., Bohlander, S. K., & Vissers, M. C. M. (2019) · Blood Cancer Journal · doi:10.1038/s41408-019-0242-4 · Cited by 54
Vitamin C supramolecular hydrogel for enhanced cancer immunotherapy
Zhang, H., Liu, K., Gong, Y., Zhu, W., Zhu, J., Pan, F., Chao, Y., Xiao, Z., Liu, Y., Wang, X., et al. (2022) · Biomaterials · doi:10.1016/j.biomaterials.2022.121673 · Cited by 52
Genetic and epigenetic evolution as a contributor to WT1-mutant leukemogenesis
Pronier, E., Bowman, R. L., Ahn, J., Glass, J. L., Kandoth, C., Merlinsky, T. R., Whitfield, J. T., Durham, B. H., Gruet, A., Somasundara, A. V. H., et al. (2018) · Blood · doi:10.1182/blood-2018-03-837468 · Cited by 52
Fat for fuel: lipid metabolism in haematopoiesis
Pernes, G., Flynn, M., Lancaster, G. I., & Murphy, A. J. (2019) · Clinical & Translational Immunology · doi:10.1002/cti2.1098 · Cited by 53
“An advance by the Morrison group demonstrates that the metabolome differs during haematopoiesis with HSCs and MPPs having similar metabolomes, while committed progenitor populations exhibit rather distinct profiles, indicating specific metabolic preferences between the haematopoietic subbranches.(109) However, because…”
BackgroundOn the physiological and cellular homeostasis of ascorbate
Przybyło, M., & Langner, M. (2020) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-020-00223-y · Cited by 53
Niederkorn, M., Ishikawa, C., Hueneman, K. M., Bartram, J., Stepanchick, E., Bennett, J., Culver-Cochran, A. E., Bolanos, L., Uible, E., Choi, K., et al. (2021) · Leukemia · doi:10.1038/s41375-021-01394-z · Cited by 35
Mitochondrial regulation of hematopoietic stem cells
Snoeck, H. (2017) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2017.12.010 · Cited by 50
High-Dose Vitamin C: Preclinical Evidence for Tailoring Treatment in Cancer Patients
Giansanti, M., Karimi, T., Faraoni, I., & Graziani, G. (2021) · Cancers · doi:10.3390/cancers13061428 · Cited by 50
Vitamin C: From nutrition to oxygen sensing and epigenetics
Kietzmann, T. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102753 · Cited by 57
Metabolic Regulation of Epigenetic Modifications and Cell Differentiation in Cancer
Saggese, P., Sellitto, A., Martinez, C. A., Giurato, G., Nassa, G., Rizzo, F. M., Tarallo, R., & Scafoglio, C. (2020) · Cancers · doi:10.3390/cancers12123788 · Cited by 46
“It has also been proposed that systemic nutritional deficiency of ascorbic acid, by causing reduced TET activity and DNA hypermethylation in hematopoietic stem cells, contributes to leukemogenesis [68].”
BackgroundInfluentialUSP15 suppresses tumor immunity via deubiquitylation and inactivation of TET2
Chen, L., Smith, M. D., Lv, L., Nakagawa, T., Li, Z., Sun, S., Brown, N. G., Xiong, Y., & Xu, Y. (2020) · Science Advances · doi:10.1126/sciadv.abc9730 · Cited by 50
Zhang, T., Huang, K., Zhu, Y., Wang, T., Shan, Y., Long, B., Li, Y., Chen, Q., Wang, P., Zhao, S., et al. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.009757 · Cited by 47
“It is noteworthy that Vc was also reported to suppress leukemogenesis through TET family enzymes, the dioxygenases that catalyze 5mC to 5hmC on DNA (20, 27, 28).”
BackgroundMechanisms involved in hematopoietic stem cell aging
Fujino, T., Asada, S., Goyama, S., & Kitamura, T. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04356-5 · Cited by 49
“In addition, two groups reported that treatment with ascorbate (vitamin C), a cofactor for Fe- and 2-oxoglutarate-dependent dioxygenases, restored 5hmC levels of Tet2−/− HSCs to suppress self-renewal and myeloid-biased differentiation [260, 261].”
BackgroundLai, W., Mo, J., Yin, J., Lyu, C., & Wang, H. (2018) · TrAC Trends in Analytical Chemistry · doi:10.1016/j.trac.2018.10.031 · Cited by 47
Roles of vitamins in stem cells
Godoy-Parejo, C., Deng, C., Zhang, Y., Liu, W., & Chen, G. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03352-6 · Cited by 45
“Vitamin C improves HSC differentiation by modulating Tet activity [180, 181], and it also increases the expression of key genes in dopaminergic neurons in the fetal brain [195], as well as trophectoderm genes like Cdx2, Eomes and Elf2 in the dif-”
BackgroundImpaired DNA demethylation of C/EBP sites causes premature agingPreprint
Schäfer, A., Mekker, B., Mallick, M., Vastolo, V., Karaulanov, E., Sebastian, D., von der Lippen, C., Epe, B., Downes, D. J., Scholz, C., et al. (2018) · Genes & Development · doi:10.1101/gad.311969.118 · Cited by 42
“Circumstantial evidence for a role in aging comes from single-Tetmutants showing increased atherosclerosis and cancer (Agathocleous et al. 2017; Cimmino et al. 2017; Fuster et al. 2017).”
BackgroundLi, Y., Hook, J. S., Qing, D., Xiao, X., Chung, S. S., Mettlen, M., Xu, L., Moreland, J. G., & Agathocleous, M. (2023) · Nature Communications · doi:10.1038/s41467-023-37567-w · Cited by 49
Self-citationVaishampayan, P., & Lee, Y. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103288 · Cited by 43
“While the involvement of these enzymes in tumor suppression is evident in various cancer models when using lower doses of VC (0.1 – 1 mM) [38 – 40], it remains unclear if these pathways contribute to acute cancer cell death with higher doses of VC [39 – 43].”
BackgroundInfluentialSami, A., Han, S., Haider, M. Z., Khizar, R., Ali, Q., Shafiq, M., Tabassum, J., KHALID, M., Javed, M. A., Sajid, M., et al. (2024) · Functional & Integrative Genomics · doi:10.1007/s10142-024-01352-9 · Cited by 43
“Furthermore, various mechanisms have healed many forms of cancer by ascorbate in recent years, including causing cancer cells to oxidate stress or boosting TET processing (Agathocleous et al. 2017).”
Lykkesfeldt, J., Carr, A. C., & Tveden‐Nyborg, P. (2025) · Pharmacological Reviews · doi:10.1016/j.pharmr.2025.100043 · Cited by 50
Fletcher, S. C., & Coleman, M. L. (2020) · Biochemical Society Transactions · doi:10.1042/bst20190333 · Cited by 44
Metabolic Reprogramming in Hematologic Malignancies: Advances and Clinical Perspectives
Yu, Z., Zhou, X., & Wang, X. (2022) · Cancer Research · doi:10.1158/0008-5472.can-22-0917 · Cited by 42
Zeng, X., Shi, C., Han, Y., Hu, K., Li, X., Wei, C., Ding, L., Cui, J., Huang, S., Xu, Y., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00669-1 · Cited by 41
“Previous studies developed a novel method with improved chromatographic separation to detect 160 metabolites in rare cell populations and identified ascorbate as an important regulator of HSC function 16,17 .”
Genome-Protecting Compounds as Potential Geroprotectors
Proshkina, E., Shaposhnikov, M. V., & Moskalev, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124484 · Cited by 42
Immunometabolic control of hematopoiesis
Hajishengallis, G., Li, X., & Chavakis, T. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2020.100923 · Cited by 43
Armstrong, N., Storey, C. M., Noll, S. E., Margulis, K., Soe, M. H., Xu, H., Yeh, B. T., Fishbein, L. M., Kebebew, E., Howitt, B. E., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110453 · Cited by 42
“Conversely, leukemogenesis is accelerated in ascorbate-depleted Gulo/− mice transplanted with Flt3ITDTet2+/−HSCs (Agathocleous et al., 2017).”
BackgroundVitamin C boosts DNA demethylation in TET2 germline mutation carriers
Taira, A., Palin, K., Kuosmanen, A., Välimäki, N., Kuittinen, O. M., Kuismin, O., Kaasinen, E., Rajamäki, K., & Aaltonen, L. A. (2023) · Clinical Epigenetics · doi:10.1186/s13148-022-01404-6 · Cited by 43
“Dietary intake of ascorbate seemed to suppress these effects [8].”
BackgroundLi, C., Wu, B., Li, Y., Liu, Y., Wang, J., Xie, J., Xu, X., Tian, X., Ye, Z., Guan, J., et al. (2022) · Blood · doi:10.1182/blood.2022016112 · Cited by 42
Lü, Z., Xie, Y., Huang, H., Jiang, K., Zhou, B., Wang, F., & Chen, T. (2020) · eLife · doi:10.7554/elife.52712 · Cited by 38
Liu, J., Hong, J., Han, H., Park, J., Kim, D., Park, H., Ko, M., Koh, Y., Shin, D., & Yoon, S. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0788-8 · Cited by 39
“SVCT2 is expressed in most haematopoietic cells, but is expressed at 14-fold higher levels in haematopoietic stem cells and multipotent progenitors (HSCs/MPPs) compared with restricted haematopoietic progenitors.(2) Based on this phenomenon, maintaining a relatively higher level of vitamin C was essential to sustain t…”
BackgroundHou, Q., Dong, Y., Yu, Q., Wang, B., Shen, L., Guo, Y., & Zhang, B. (2020) · The FASEB Journal · doi:10.1096/fj.201902573rr · Cited by 39
Gu, H., Chen, C., Hao, X., Su, N., Huang, D., Zou, Y., Lin, S., Chen, X., Zheng, D., Liu, L., et al. (2020) · Blood · doi:10.1182/blood.2019003940 · Cited by 36
Giafaglione, J. M., Crowell, P. D., Delcourt, A. M. L., Hashimoto, T., Ha, S. M., Atmakuri, A., Nunley, N. M., Dang, R. M. A., Tian, M., Diaz, J. A., et al. (2023) · Nature Cell Biology · doi:10.1038/s41556-023-01274-x · Cited by 40
Stangis, M. M., Chen, Z., Min, J., Glass, S. E., Jackson, J. O., Radyk, M. D., Hoi, X. P., Brennen, W. N., Yu, M., Dinh, H. Q., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-1550 · Cited by 37
Potential application of cell reprogramming techniques for cancer research
Saito, S., Lin, Y., Nakamura, Y., Eckner, R., Wuputra, K., Kuo, K., Lin, C., & Yokoyama, K. K. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2924-7 · Cited by 38
Xie, J., Sheng, M., Rong, S., Zhou, D., Wang, C., Wu, W., Huang, J., Sun, Y., Wang, Y., Chen, P., et al. (2023) · Leukemia · doi:10.1038/s41375-023-02055-z · Cited by 39
“Data are mean ± s.e.m., * P < 0.05; ** P < 0.01; “ ns ” : not signi fi cant.”
InfluentialBewersdorf, J. P., Ardasheva, A., Podoltsev, N. A., Singh, A., Biancon, G., Halene, S., & Zeidan, A. M. (2019) · Blood Reviews · doi:10.1016/j.blre.2019.100587 · Cited by 37
Interplay between Clonal Hematopoiesis of Indeterminate Potential and Metabolism
Lee, M. K. S., Dragoljevic, D., Veiga, C. B., Wang, N., Yvan‐Charvet, L., & Murphy, A. J. (2020) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2020.02.005 · Cited by 37
Retinoids in the Pathogenesis and Treatment of Liver Diseases
Melis, M., Tang, X., Trasino, S. E., & Gudas, L. J. (2022) · Nutrients · doi:10.3390/nu14071456 · Cited by 37
“Vitamins, including vitamin A [1–3], vitamin B3 [4], and vitamin C [5] are capable, through various signaling pathways, of changing the epigenetic states of stem cells.”
BackgroundSong, C., Wang, L., Wu, X., Wang, K., Xie, D., Xiao, Q., Li, S., Jiang, K., Liao, L., Yates, J. R., et al. (2018) · Cancer Research · doi:10.1158/0008-5472.can-17-3091 · Cited by 37
“Importantly, recent studies demonstrate that restoration of TET functions by genetic or pharmacological (ascorbate) methods itself could suppress cancer progression (43, 44).”
Ascorbate: antioxidant and biochemical activities and their importance for in vitro models
Zhitkovich, A. (2021) · Archives of Toxicology · doi:10.1007/s00204-021-03167-0 · Cited by 35
Two Distinct Faces of Vitamin C: AA vs. DHA
Ferrada, L., Magdalena, R., Barahona, M. J., Ramírez, E., Sanzana, C., Gutiérrez, J. L., & Nualart, F. (2021) · Antioxidants · doi:10.3390/antiox10020215 · Cited by 33
“Additionally, the incubation of vitamin C with the catalytic domain of TET2 showed a progressive extinction of the latter’s intrinsic fluorescence (determined by the presence of tyrosine residues that intrinsically fluoresce) in a concentration-dependent manner, thus suggesting a direct interaction between these two m…”
BackgroundInfluentialLC-MS-Based Targeted Metabolomics for FACS-Purified Rare Cells
Schönberger, K., Mitterer, M., Glaser, K. M., Stecher, M., Hobitz, S., Schain-Zota, D., Schuldes, K., Lämmermann, T., Rambold, A. S., Cabezas‐Wallscheid, N., et al. (2023) · Analytical Chemistry · doi:10.1021/acs.analchem.2c04396 · Cited by 33
Li, A. M., & Ye, J. (2023) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-062822-120857 · Cited by 31
Chromosomal Instability in Acute Myeloid Leukemia
Lisboa, M. D. O., Brofman, P. R. S., Schmid-Braz, A. T., Pozzo, A. R., & Mai, S. (2021) · Cancers · doi:10.3390/cancers13112655 · Cited by 33
Hematopoiesis during Ontogenesis, Adult Life, and Aging
Belyavsky, A. V., Петинати, Н. А., & Дризе, Н. И. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179231 · Cited by 37
Role of TET dioxygenases in the regulation of both normal and pathological hematopoiesis
Joshi, K., Zhang, L., Breslin, P., Kini, A. R., & Zhang, J. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02496-x · Cited by 31
Inflammageing and clonal haematopoiesis interplay and their impact on human disease
Hajishengallis, G., & Chavakis, T. (2026) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00936-y · Cited by 37
The hematopoietic stem cell diet
Wilkinson, A. C., & Yamazaki, S. (2018) · International Journal of Hematology · doi:10.1007/s12185-018-2451-1 · Cited by 30
Challenges in Studying Stem Cell Metabolism
Perez-Ramirez, C. A., & Christofk, H. R. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.02.016 · Cited by 30
Yan, Y., Huang, Z., Zhu, Z. Y., Cui, Y., Li, M., Huang, R., Yan, J., & Shen, B. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00667 · Cited by 29
“In leukemia, vitamin C has been confirmed to suppress leukemogenesis by promoting TET activity (26).”
BackgroundImplications of Clonal Hematopoiesis for Precision Oncology
Miller, P. G., & Steensma, D. P. (2020) · JCO Precision Oncology · doi:10.1200/po.20.00144 · Cited by 30
WIND1 induces dynamic metabolomic reprogramming during regeneration in Brassica napus
Iwase, A., Mita, K., Favero, D. S., Mitsuda, N., Sasaki, R., Kobayshi, M., Takebayashi, Y., Kojima, M., Kusano, M., Oikawa, A., et al. (2018) · Developmental Biology · doi:10.1016/j.ydbio.2018.07.006 · Cited by 29
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
