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.”
NAD + repletion improves mitochondrial and stem cell function and enhances life span in mice
Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., D’Amico, D., Ropelle, E. R., Lutolf, M. P., Aebersold, R., et al. (2016) · Science · doi:10.1126/science.aaf2693 · Cited by 1,255 · cited 1×
“It is generally unknown whether dietary changes alter stem cell function due to changes in metabolite levels; however, muscle stem cell aging is regulated by changes in NAD + levels 4 .”
Noguchi, K., Gel, Y. R., Brunner, E., & Konietschke, F. (2012) · Journal of Statistical Software · doi:10.18637/jss.v050.i12 · Cited by 1,146
Simsek, T., Kocabas, F., Zheng, J., DeBerardinis, R. J., Mahmoud, A. I., Olson, E. N., Schneider, J. W., Zhang, C. C., & Sadek, H. A. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.07.011 · Cited by 1,101 · cited 1×
“Others have studied stem cell metabolism by characterizing the phenotypes of knockout mice or metabolism in culture 11 .”
Self-citationIntracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells
Carey, B. W., Finley, L. W. S., Cross, J. R., Allis, C. D., & Thompson, C. B. (2015) · Nature · doi:10.1038/nature13981 · Cited by 1,007
Quivoron, C., Couronné, L., Della Valle, V., Lopez, C. K., Plo, I., Wagner-Ballon, O., Do Cruzeiro, M., Delhommeau, F., Arnulf, B., Stern, M.-H., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.06.003 · Cited by 924 · cited 2×
“Consistent with prior studies 27–29 , conditional deletion of Tet2 in adult haematopoietic cells significantly increased HSC frequency and function (Extended Data Fig.”
Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH
Yun, J., Mullarky, E., Lu, C., Bosch, K. N., Kavalier, A., Rivera, K., Roper, J., Chio, I. I. C., Giannopoulou, E. G., Rago, C., et al. (2015) · Science · doi:10.1126/science.aaa5004 · Cited by 913 · cited 1×
“In clinical trials, oral ascorbate administration failed to benefit patients with established cancers 42 , though supraphysiological ascorbate concentrations can slow the growth of some cancers in mice by causing oxidative stress 43,44 .”
Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells
Blaschke, K., Ebata, K. T., Karimi, M. M., Zepeda-Martínez, J. A., Goyal, P., Mahapatra, S., Tam, A., Laird, D. J., Hirst, M., Rao, A., et al. (2013) · Nature · doi:10.1038/nature12362 · Cited by 865
Takubo, K., Nagamatsu, G., Kobayashi, C. I., Nakamura‐Ishizu, A., Kobayashi, H., Ikeda, E., Goda, N., Rahimi, Y., Johnson, R. S., Soga, T., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2012.10.011 · Cited by 864 · cited 1×
“Metabolomics has been performed on haematopoietic stem/ progenitor cells either by isolating large numbers of heterogeneous Lineage − Sca-1 + c-kit + (LSK) cells 9 or by pooling HSCs from 120 mice to perform a single experiment 10 .”
Chen, Q., Espey, M. G., Sun, A. Y., Pooput, C., Kirk, K. L., Krishna, M. C., Khosh, D. B., Drisko, J., & Levine, M. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0804226105 · Cited by 854 · cited 1×
“In clinical trials, oral ascorbate administration failed to benefit patients with established cancers 42 , though supraphysiological ascorbate concentrations can slow the growth of some cancers in mice by causing oxidative stress 43,44 .”
Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis
Busque, L., Patel, J. P., Figueroa, M. E., Vasanthakumar, A., Provost, S., Hamilou, Z., Mollica, L., Li, J., Viale, A., Heguy, A., et al. (2012) · Nature Genetics · doi:10.1038/ng.2413 · Cited by 830 · 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 .”
Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal
Acar, M., Kocherlakota, K. S., Murphy, M. M., Peyer, J. G., Oguro, H., Inra, C. N., Jaiyeola, C., Zhao, Z., Luby‐Phelps, K., & Morrison, S. J. (2015) · Nature · doi:10.1038/nature15250 · Cited by 729
Self-citationGenetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies
Abdel-Wahab, O., Mullally, A., Hedvat, C., Garcia-Manero, G., Patel, J., Wadleigh, M., Malinge, S., Yao, J., Kilpivaara, O., Bhat, R., et al. (2009) · Blood · doi:10.1182/blood-2009-03-210039 · Cited by 727 · 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 .”
Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia
Jan, M., Snyder, T. M., Corces-Zimmerman, M. R., Vyas, P., Weissman, I. L., Quake, S. R., & Majeti, R. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004315 · Cited by 721
Moertel, C. G., Fleming, T. R., Creagan, E. T., Rubin, J., O'Connell, M. J., & Ames, M. M. (1985) · New England Journal of Medicine · doi:10.1056/nejm198501173120301 · Cited by 637 · cited 1×
“In clinical trials, oral ascorbate administration failed to benefit patients with established cancers 42 , though supraphysiological ascorbate concentrations can slow the growth of some cancers in mice by causing oxidative stress 43,44 .”
Ko, M., Bandukwala, H. S., An, J., Lamperti, E. D., Thompson, E. C., Hastie, R., Tsangaratou, A., Rajewsky, K., Koralov, S. B., & Rao, A. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1112317108 · Cited by 616 · cited 1×
“This is consistent with the conclusion that ascorbate promotes Tet2 function as Tet2 deficiency promotes monocytic differentiation and reduces erythroid differentiation in culture 28,34 .”
Yin, R., Mao, S.-Q., Zhao, B., Chong, Z., Yang, Y., Zhao, C., Zhang, D., Huang, H., Gao, J., Li, Z., et al. (2013) · Journal of the American Chemical Society · doi:10.1021/ja4028346 · Cited by 609 · cited 1×
“…to detect an effect of ascorbate depletion on the function of these enzymes, they could potentially contribute to the effects of ascorbate depletion on HSCs. Ascorbate promotes the activity of Tet enzymes in culture 7,21–23 , though it is not clear whether ascorbate limits Tet function in vivo.”
Khaw, K., Bingham, S. A., Welch, A. A., Luben, R., Wareham, N. J., Oakes, S., & Day, N. (2001) · The Lancet · doi:10.1016/s0140-6736(00)04128-3 · Cited by 576 · cited 1×
“In western countries, plasma ascorbate levels vary 10-fold among individuals 33 , and the lowest quartile of men have a significantly higher risk of mortality from cancer 38,39 .”
Doulatov, S. R., Notta, F., Eppert, K., Nguyen, L. T., Ohashi, P. S., & Dick, J. E. (2010) · Nature Immunology · doi:10.1038/ni.1889 · Cited by 566
Schleicher, R. L., Carroll, M. D., Ford, E. S., & Lacher, D. A. (2009) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.27016 · Cited by 504 · cited 2×
“Ascorbate levels in Gulo −/− mice were therefore similar to those observed in 5% of people in western countries 33 .”
Wang, T., Chen, K., Zeng, X., Yang, J., Wu, Y., Shi, X., Qin, B., Zeng, L., Esteban, M. A., Pan, G., et al. (2011) · Cell Stem Cell · doi:10.1016/j.stem.2011.10.005 · Cited by 458 · cited 2×
“Addition of ascorbate to culture medium promotes pluripotency by stimulating Jumonji histone demethylase activity 16 and by stimulating Tet activity 7,22 .”
Bethesda proposals for classification of nonlymphoid hematopoietic neoplasms in mice
Kogan, S. C., Ward, J. M., Anver, M. R., Berman, J. J., Brayton, C., Cardiff, R. D., Carter, J. S., de Coronado, S., Downing, J. R., Fredrickson, T. N., et al. (2002) · Blood · doi:10.1182/blood.v100.1.238 · Cited by 418
Minor, E. A., Court, B. L., Young, J. I., & Wang, G. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.c113.464800 · Cited by 413 · cited 1×
“…to detect an effect of ascorbate depletion on the function of these enzymes, they could potentially contribute to the effects of ascorbate depletion on HSCs. Ascorbate promotes the activity of Tet enzymes in culture 7,21–23 , though it is not clear whether ascorbate limits Tet function in vivo.”
Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function
Garaycoechea, J. I., Crossan, G. P., Langevin, F., Daly, M. G., Arends, M. J., & Patel, K. J. (2012) · Nature · doi:10.1038/nature11368 · Cited by 390 · cited 1×
“Genetic changes in metabolic enzymes can alter stem cell function 1 and cause oncogenic transformation 2 .”
Sotiriou, S., Gispert, S., Cheng, J., Wang, Y., Chen, A., Hoogstraten-Miller, S., Miller, G. F., Kwon, O., Levine, M., Guttentag, S. H., et al. (2002) · Nature Medicine · doi:10.1038/0502-514 · Cited by 367
Dependence of Mouse Embryonic Stem Cells on Threonine Catabolism
Wang, J., Alexander, P. B., Wu, L. C., Hammer, R. E., Cleaver, O. B., & McKnight, S. L. (2009) · Science · doi:10.1126/science.1173288 · Cited by 365 · cited 1×
“Differentiation in vivo is accompanied by metabolic changes 5 and experimental manipulation of metabolite levels in culture can modulate pluripotent stem cell differentiation 6–8 .”
(2003) · PubMed · Cited by 350
Mullen, A. R., Hu, Z., Shi, X., Jiang, L., Boroughs, L. K., Kovacs, Z., Boriack, R., Rakheja, D., Sullivan, L. B., Linehan, W. M., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.04.037 · Cited by 337 · cited 1×
“The flow rate was 0.5 ml/min, the column was at 35°C and the samples in the autosampler were at 4°C. Mass spectrometry was performed with a triple quadrupole mass spectrometer (AB Sciex QTRAP 5500) in multiple reaction monitoring (MRM) mode as described 53 , with some modifications.”
InfluentialSelf-citationVitamin C modulates TET1 function during somatic cell reprogramming
Chen, J., Guo, L., Zhang, L., Wu, H., Yang, J., Liu, H., Wang, X., Hu, X., Gu, T., Zhou, Z., et al. (2013) · Nature Genetics · doi:10.1038/ng.2807 · Cited by 322 · cited 1×
“Addition of ascorbate to culture medium promotes pluripotency by stimulating Jumonji histone demethylase activity 16 and by stimulating Tet activity 7,22 .”
Kivirikko, K. I., Myllylä, R., & Pihlajaniemi, T. (1989) · The FASEB Journal · doi:10.1096/fasebj.3.5.2537773 · Cited by 320 · cited 1×
“Although ascorbate promotes the activity of prolyl 4-hydroxylase during collagen synthesis 17 , we did not detect a pronounced loss of bone collagen in ascorbate-depleted mice (Extended Data Fig.”
Regulation of the epigenome by vitamin C
Young, J. I., Züchner, S., & Wang, G. (2015) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071714-034228 · Cited by 319 · cited 1×
“Ascorbate is a cofactor for several α -ketoglutarate-dependent dioxygenases 15 , including Jumonji histone demethylases 16 ; however, ascorbate depletion did not significantly increase the levels of several histone methylation marks (Extended Data Fig.”
Ascorbic acid and carnitine biosynthesis
Rebouche, C. (1991) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/54.6.1147s · Cited by 276 · cited 1×
“Ascorbate can regulate hydroxylase enzymes during carnitine biosynthesis in culture 18 ; however, we did not detect any effect of ascorbate depletion on carnitine or acetylcarnitine levels in haematopoietic cells (Extended Data Fig.”
Ascorbic acid and dehydroascorbic acid analyses in biological samples
Washko, P. W., Welch, R. W., Dhariwal, K. R., Wang, Y., & Levine, M. (1992) · Analytical Biochemistry · doi:10.1016/0003-2697(92)90131-p · Cited by 270 · cited 1×
“To measure ascorbate, 15 pmoles 13 C ascorbate (Sigma) were added to the 80% methanol as an internal standard and 1 mM EDTA was added to prevent ascorbate oxidation 52 .”
Aortic wall damage in mice unable to synthesize ascorbic acid
Maeda, N., Hagihara, H., Nakata, Y., Hiller, S., Wilder, J., & Reddick, R. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.2.841 · Cited by 260 · cited 1×
“Gulo −/− 48 , Tet2 fl 27 , Flt3 ITD 49 , Slc23a2 −/− 50 and Mx1-Cre 51 mice were previously described.”
Gene Expression Commons: An Open Platform for Absolute Gene Expression Profiling
Seita, J., Sahoo, D., Rossi, D. J., Bhattacharya, D., Serwold, T. F., Inlay, M. A., Ehrlich, L. I. R., Fathman, J. W., Dill, D. L., & Weissman, I. L. (2012) · PLoS ONE · doi:10.1371/journal.pone.0040321 · Cited by 258 · cited 1×
“Slc23a1 and Gulo are not expressed by haematopoietic cells 13 .”
TET1 is a tumor suppressor of hematopoietic malignancy
Cimmino, L., Dawlaty, M. M., Ndiaye‐Lobry, D., Yap, Y. S., Bakogianni, S., Yu, Y., Bhattacharyya, S., Shaknovich, R., Geng, H., Lobry, C., et al. (2015) · Nature Immunology · doi:10.1038/ni.3148 · Cited by 242 · cited 1×
“8g), this suggests that ascorbate depletion promoted B lymphopoiesis through Tet2 independent mechanisms, potentially through reduced Tet1 function, which regulates B lymphopoiesis 36 .”
Lee, B. H., Tóthová, Z., Levine, R. L., Anderson, K., Buza-Vidas, N., Cullen, D. E., McDowell, E. P., Adelsperger, J., Fröhling, S., Huntly, B. J. P., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.08.031 · Cited by 242 · cited 1×
“Gulo −/− 48 , Tet2 fl 27 , Flt3 ITD 49 , Slc23a2 −/− 50 and Mx1-Cre 51 mice were previously described.”
Shih, A. H., Jiang, Y., Meydan, C., Shank, K., Pandey, S., Barreyro, L., Antony-Debre, I., Viale, A., Socci, N., Sun, Y., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.03.009 · Cited by 236 · cited 5×
“CD48 + CD150 − LSK HPC cells, which can initiate AML from Flt3 ITD ;Tet2 Δ/+ cells 31 , expanded to a significantly greater extent in the bone marrow (Extended Data Fig.”
InfluentialVitamin C increases viral mimicry induced by 5-aza-2′-deoxycytidine
Liu, M., Ohtani, H., Zhou, W., Ørskov, A. D., Charlet, J., Zhang, Y. W., Shen, H., Baylin, S. B., Liang, G., Grønbæk, K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1612262113 · Cited by 225 · cited 1×
“Humans with haematological malignancies have significantly lower serum ascorbate levels as compared to healthy controls 40,41 .”
Acute loss of TET function results in aggressive myeloid cancer in mice
An, J., González‐Avalos, E., Chawla, A., Jeong, M., López-Moyado, I. F., Li, W., Goodell, M. A., Chávez, L., Ko, M., & Rao, A. (2015) · Nature Communications · doi:10.1038/ncomms10071 · Cited by 215 · cited 3×
“Reduced Tet2 31 , or Tet2 and Tet3 37 , function promote AML development.”
Pronier, E., Almire, C., Mokrani, H., Vasanthakumar, A., Simon, A., Monte-Mór, B. D. C. R., Massé, A., Couedic, J. P. L., Pendino, F., Carbonne, B., et al. (2011) · Blood · doi:10.1182/blood-2010-12-324707 · Cited by 204 · cited 1×
“This is consistent with the conclusion that ascorbate promotes Tet2 function as Tet2 deficiency promotes monocytic differentiation and reduces erythroid differentiation in culture 28,34 .”
Vitamin C status and mortality in US adults
Loria, C. M., Klag, M. J., Caulfield, L. E., & Whelton, P. K. (2000) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/72.1.139 · Cited by 188 · cited 1×
“In western countries, plasma ascorbate levels vary 10-fold among individuals 33 , and the lowest quartile of men have a significantly higher risk of mortality from cancer 38,39 .”
Metabolic differentiation in the embryonic retina
Agathocleous, M., Love, N. K., Randlett, O., Harris, J. J., Liu, J., Murray, A. J., & Harris, W. A. (2012) · Nature Cell Biology · doi:10.1038/ncb2531 · Cited by 182
Self-citationVitamin C Promotes Maturation of T-Cells
Manning, J., Mitchell, B., Appadurai, D. A., Shakya, A., Pierce, L. J., Wang, H., Nganga, V. K., Swanson, P. C., May, J. M., Tantin, D. R., et al. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4988 · Cited by 180 · cited 1×
“3u), consistent with a known requirement for ascorbate in thymocyte maturation 14 .”
Self-citationDietary and Metabolic Control of Stem Cell Function in Physiology and Cancer
Mihaylova, M. M., Sabatini, D. M., & Yilmaz, Ö. H. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.02.008 · Cited by 158 · cited 1×
“Dietary changes alter stem cell function in multiple systems by regulating signalling, for example by insulin/IGF 3 .”
May, J. M. (2011) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2011.01350.x · Cited by 108 · cited 18×
“Therefore, ascorbate accumulation in HSCs was likely due to high Slc23a2 expression.”
InfluentialAscorbic acid serum levels are reduced in patients with hematological malignancies
Huijskens, M. J. A. J., Wodzig, W. K. W. H., Walczak, M., Germeraad, W. T. V., & Bos, G. M. J. (2016) · Results in Immunology · doi:10.1016/j.rinim.2016.01.001 · Cited by 106 · cited 1×
“Humans with haematological malignancies have significantly lower serum ascorbate levels as compared to healthy controls 40,41 .”
Adult hematopoietic stem cells lacking Hif-1α self-renew normally
Vukovic, M., Sepúlveda, C., Subramani, C., Guitart, A. V., Mohr, J., Allen, L., Panagopoulou, T. I., Paris, J., Lawson, H., Villacreces, A., et al. (2016) · Blood · doi:10.1182/blood-2015-10-677138 · Cited by 88 · cited 1×
“Ascorbate can act as a co-factor for prolyl hydroxylases that degrade Hypoxia Inducible Factors (HIF) 19 but HIF-1 α and HIF-2 α are not required for HSC function 20 .”
Naka, K., Jomen, Y., Ishihara, K., Kim, J., Ishimoto, T., Bae, E., Mohney, R. P., Stirdivant, S. M., Oshima, H., Oshima, M., et al. (2015) · Nature Communications · doi:10.1038/ncomms9039 · Cited by 64 · cited 1×
“Metabolomics has been performed on haematopoietic stem/ progenitor cells either by isolating large numbers of heterogeneous Lineage − Sca-1 + c-kit + (LSK) cells 9 or by pooling HSCs from 120 mice to perform a single experiment 10 .”
Flagged first, then by citations
Cited by
Sorted by citations
Lymph protects metastasizing melanoma cells from ferroptosis
Ubellacker, J. M., Tasdogan, A., Ramesh, V., Shen, B., Mitchell, E. C., Martin-Sandoval, M. S., Gu, Z., McCormick, M. L., Durham, A. B., Spitz, D. R., et al. (2020) · Nature · doi:10.1038/s41586-020-2623-z · Cited by 916
Self-citationAscorbic acid metabolism and functions: A comparison of plants and mammals
Smirnoff, N. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.03.033 · Cited by 683
The Complex Interplay between Antioxidants and ROS in Cancer
Harris, I. S., & DeNicola, G. M. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.03.002 · Cited by 659
“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
Reid, M. A., Dai, Z., & Locasale, J. W. (2017) · Nature Cell Biology · doi:10.1038/ncb3629 · Cited by 515
The ageing epigenome and its rejuvenation
Zhang, W., Qu, J., Liu, G.-H., & Belmonte, J. C. I. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0204-5 · Cited by 458
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
