Abstract
Vitamin C has been demonstrated to regulate hematopoietic stem cell frequencies and leukemogenesis by augmenting and restoring Ten-Eleven Translocation-2 (TET2) function, potentially acting as a promising adjunctive therapeutic agent for leukemia. However, glucose transporter 3 (GLUT3) deficiency in acute myeloid leukemia (AML) impedes vitamin C uptake and abolishes the clinical benefit of vitamin C. In this study, we aimed to investigate the therapeutic value of GLUT3 restoration in AML. In vitro GLUT3 restoration was conducted with the transduction of GLUT3-overexpressing lentivirus or the pharmacological salvage with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) treatment to OCI-AML3, a naturally GLUT3-deficient AML cell line. The effects of GLUT3 salvage were further confirmed in patient-derived primary AML cells. Upregulation of GLUT3 expression made AML cells successfully augment TET2 activity and enhanced the vitamin C-induced anti-leukemic effect. Pharmacological GLUT3 salvage has the potential to overcome GLUT3 deficiency in AML and improves the antileukemic effect of vitamin C treatments.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The RNA-seq datasets generated and analyzed during the current study are available from the [Gene Expression Omnibus, GSE216576] repository.
References
Rasmussen KD, Helin K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 2016;30:733–50.
Scourzic L, Mouly E, Bernard OA. TET proteins and the control of cytosine demethylation in cancer. Genome Med. 2015;7:9.
Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014;28:241–7.
Cancer Genome Atlas Research N, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.
Palomero T, Couronne L, Khiabanian H, Kim MY, Ambesi-Impiombato A, Perez-Garcia A, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014;46:166–70.
Agathocleous M, Meacham CE, Burgess RJ, Piskounova E, Zhao Z, Crane GM, et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature. 2017;549:476–81.
Pastor WA, Aravind L, Rao A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol. 2013;14:341–56.
Liu M, Ohtani H, Zhou W, Orskov AD, Charlet J, Zhang YW, et al. Vitamin C increases viral mimicry induced by 5-aza-2’-deoxycytidine. Proc Natl Acad Sci USA. 2016;113:10238–44.
Ottone T, Faraoni I, Fucci G, Divona M, Travaglini S, De Bellis E, et al. Vitamin C deficiency in patients with acute myeloid leukemia. Front Oncol. 2022;12:890344.
Schonberger K, Cabezas-Wallscheid N. Vitamin C: C-ing a new way to fight leukemia. Cell Stem Cell. 2017;21:561–3.
Aldoss I, Mark L, Vrona J, Ramezani L, Weitz I, Mohrbacher AM, et al. Adding ascorbic acid to arsenic trioxide produces limited benefit in patients with acute myeloid leukemia excluding acute promyelocytic leukemia. Ann Hematol. 2014;93:1839–43.
Liu J, Hong J, Han H, Park J, Kim D, Park H, et al. Decreased vitamin C uptake mediated by SLC2A3 promotes leukaemia progression and impedes TET2 restoration. Br J Cancer. 2020;122:1445–52.
Chou TC. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 2010;70:440–6.
Borowicz S, Van Scoyk M, Avasarala S, Karuppusamy Rathinam MK, Tauler J, Bikkavilli RK, et al. The soft agar colony formation assay. J Vis Exp. 2014:e51998.
Tokuyama M, Kong Y, Song E, Jayewickreme T, Kang I, Iwasaki A. ERVmap analysis reveals genome-wide transcription of human endogenous retroviruses. Proc Natl Acad Sci USA. 2018;115:12565–72.
Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 2004;5:R80.
Yin R, Mao SQ, Zhao B, Chong Z, Yang Y, Zhao C, et al. Ascorbic acid enhances Tet-mediated 5-methylcytosine oxidation and promotes DNA demethylation in mammals. J Am Chem Soc. 2013;135:10396–403.
Cimmino L, Dolgalev I, Wang Y, Yoshimi A, Martin GH, Wang J, et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell. 2017;170:1079–95.e20.
Smith-Diaz CC, Magon NJ, McKenzie JL, Hampton MB, Vissers MCM, Das AB. Ascorbate inhibits proliferation and promotes myeloid differentiation in TP53-mutant leukemia. Front Oncol. 2021;11:709543.
Brabson JP, Leesang T, Yap YS, Wang J, Lam MQ, Fang B, et al. Oxidized mC modulates synthetic lethality to PARP inhibitors for the treatment of leukemia. Cell Rep. 2023;42:112027.
Chen WL, Wang YY, Zhao A, Xia L, Xie G, Su M, et al. Enhanced fructose utilization mediated by SLC2A5 is a unique metabolic feature of acute myeloid leukemia with therapeutic potential. Cancer Cell. 2016;30:779–91.
De Ravin SS, Wu X, Moir S, Anaya-O'Brien S, Kwatemaa N, Littel P, et al. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med. 2016;8:335ra57.
Dai W, Xu Y, Mo S, Li Q, Yu J, Wang R, et al. GLUT3 induced by AMPK/CREB1 axis is key for withstanding energy stress and augments the efficacy of current colorectal cancer therapies. Signal Transduct Target Ther. 2020;5:177.
Dosedel M, Jirkovsky E, Macakova K, Krcmova LK, Javorska L, Pourova J, et al. Vitamin C-sources, physiological role, kinetics, deficiency, use, toxicity, and determination. Nutrients. 2021;13:615.
Vera JC, Rivas CI, Zhang RH, Farber CM, Golde DW. Human HL-60 myeloid leukemia cells transport dehydroascorbic acid via the glucose transporters and accumulate reduced ascorbic acid. Blood. 1994;84:1628–34.
Carita AC, Fonseca-Santos B, Shultz JD, Michniak-Kohn B, Chorilli M, Leonardi GR. Vitamin C: one compound, several uses. Advances for delivery, efficiency and stability. Nanomedicine. 2020;24:102117.
Halliwell B. Vitamin C: antioxidant or pro-oxidant in vivo? Free Radic Res. 1996;25:439–54.
Visnjic D, Lalic H, Dembitz V, Tomic B, Smoljo T. AICAr, a widely used AMPK activator with important AMPK-independent effects: a systematic review. Cells. 2021;10:1095.
Van Den Neste E, Cazin B, Janssens A, Gonzalez-Barca E, Terol MJ, Levy V, et al. Acadesine for patients with relapsed/refractory chronic lymphocytic leukemia (CLL): a multicenter phase I/II study. Cancer Chemother Pharm. 2013;71:581–91.
Cluzeau T, Furstoss N, Savy C, El Manaa W, Zerhouni M, Blot L, et al. Acadesine circumvents azacitidine resistance in myelodysplastic syndrome and acute myeloid leukemia. Int J Mol Sci. 2019;21:164.
Penugurti V, Mishra YG, Manavathi B. AMPK: An odyssey of a metabolic regulator, a tumor suppressor, and now a contextual oncogene. Biochim Biophys Acta Rev Cancer. 2022;1877:188785.
Wu D, Hu D, Chen H, Shi G, Fetahu IS, Wu F, et al. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature. 2018;559:637–41.
Acknowledgements
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT; grant no. NRF-2020R1C1C1011110).
Author information
Authors and Affiliations
Contributions
Conception and design: JH and JL. Development of methodology: JL and SM. Acquisition of data: JL and SM. Analysis and interpretation of data: JL Writing, review, and/or revision of the manuscript: JL, SP, MK, and JH. Administrative, technical, or material support: NJ and SM. Study supervision: JH, YK, DY-S, JM-B, and SS-Y. Performed research: JL, JP, SM, NJ, DK, and EP.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Liu, J., Min, S., Kim, D. et al. Pharmacological GLUT3 salvage augments the efficacy of vitamin C-induced TET2 restoration in acute myeloid leukemia. Leukemia 37, 1638–1648 (2023). https://doi.org/10.1038/s41375-023-01954-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41375-023-01954-5