Abstract
Background: Two new studies in Nature and Cell, from Agathocleous et al. (2017) and Cimmino et al. (2017), respectively, showed that vitamin C regulates HSC function and suppresses leukemogenesis by modulating Tet2 activity. However, little is known about the relationship between vitamin C transporter and hematological malignancies.
Purpose: In this study, we investigated the role of SLC2A3, a gene that encode GLUT3 which mainly transport glucose and oxidized form vitamin C, in hematological malignancies. Through this research we identified a set of biomarkers which can predict the effect of vitamin C treatment and develop stagey to improve this putative innovative treatment.
Results: We analyzed gene expression patterns of the major GLUT family genes in primary AML blast cells using previously published microarray datasets (GSE37307) and (GSE9476) and determined that SLC2A3 gene expression was significantly decreased in blast cells compared with normal hematopoietic cells. By contrast, expression of SLC2A1, SLC2A2 and SLC23A2 was not significant different in between primary AML cells and normal hematopoietic cells. Next, we analyzed the relevance of SLC2A3 expression to the survival of AML patients from TCGA and TARGET database and found that below-median SLC2A3 expression was associated with inferior overall survival. Subsequently, we detected the SLC2A3 mRNA expression level on 4 AML cell lines and 3 DLBCL cell lines, there were very low expression level on OCI-AML-3 and OCI-LY1. To check whether decreased expression of SLC2A3 has an impact on the Vitamin C effect, we treated the 7 cell lines with dose dependent vitamin C, up to 500 μM, 48 hours. The cell viability assay showed that OCI-AML-3 and OCI-LY1 have no response to Vitamin C, however the proliferation of NB4, HEL, HL60, OCI-LY19 and Toledo was suppressed by 250 μM Vitamin C.
Conclusions: SLC2A3 expression was decreased in AML blast cell and down regulation of SLC2A3 was closely associated with the poor outcomes of AML patients. In vitro study showed that SLC2A3 was essential for the effect of Vitamin C. Therefore, SLC2A3 could be a potential biomarker to predict the effect of Vitamin C treatment. In addition, through targeting SLC2A3, efficacy of Vitamin C treatment could be improved.
Citation Format: Jun Liu, Junshik Hong, Kwangsung Ahn, Sungsoo Yoon. Decreased vitamin C uptake mediated by SLC2A3 promotes leukemia progression and impedes Tet2 restoration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3612.
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