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ACUTE MYELOID LEUKEMIA

Pharmacological GLUT3 salvage augments the efficacy of vitamin C-induced TET2 restoration in acute myeloid leukemia

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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.

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Fig. 1: GLUT3 salvage augmented the efficacy of vitamin C treatment.
Fig. 2: GLUT3 salvage with vitamin C treatment altered the gene expression landscape of OCI-AML3 cells to a vitamin C-responsive profile.
Fig. 3: AICAR pharmacologically turns on GLUT3 expression.
Fig. 4: Pharmacological GLUT3 salvage using AICAR augmented the efficacy of vitamin C treatment.
Fig. 5: Upregulation of GLUT3 was the primary target of AICAR.
Fig. 6: AICAR pharmacologically salvages GLUT3 expression in patient-derived primary AML blast cells.
Fig. 7: Pharmacological GLUT3 salvage augments the efficacy of vitamin C-induced TET2 restoration in AML.

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Data availability

The RNA-seq datasets generated and analyzed during the current study are available from the [Gene Expression Omnibus, GSE216576] repository.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT; grant no. NRF-2020R1C1C1011110).

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Authors and Affiliations

  1. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea

    Jun Liu, Dongchan Kim, Jihyun Park, Eunchae Park, Youngil Koh, Dong-Yeop Shin, Ja Min Byun, Sung-Soo Yoon & Junshik Hong

  2. Center for Medical Innovation, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea

    Jun Liu, Suji Min, Dongchan Kim, Jihyun Park, Eunchae Park, Youngil Koh, Dong-Yeop Shin, Ja Min Byun, Sung-Soo Yoon & Junshik Hong

  3. Liangzhu Laboratory, Zhejiang University, Hangzhou, China

    Jun Liu & Shanshan Pei

  4. Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea

    Youngil Koh, Dong-Yeop Shin, Ja Min Byun, Sung-Soo Yoon & Junshik Hong

  5. Biomedical Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea

    Youngil Koh, Dong-Yeop Shin, Ja Min Byun, Sung-Soo Yoon & Junshik Hong

  6. School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea

    Myunggon Ko

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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.

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Correspondence to Junshik Hong.

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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

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