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Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase

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Abstract

Iron overload remains a concern in myelodysplastic syndrome (MDS) patients. Iron chelation therapy (ICT) thus plays an integral role in the management of these patients. Moreover, ICT has been shown to prolong leukemia-free survival in MDS patients; however, the mechanisms responsible for this effect are unclear. Iron is a key molecule for regulating cytosolic aconitase 1 (ACO1). Additionally, the mutation of isocitrate dehydrogenase (IDH), the enzyme downstream of ACO1 in the TCA cycle, is associated with epigenetic abnormalities secondary to 2-hydroxyglutarate (2-HG) and DNA methylation. However, epigenetic abnormalities observed in many MDS patients occur without IDH mutation. We hypothesized that iron itself activates the ACO1-IDH pathway, which may increase 2-HG and DNA methylation, and eventually contribute to leukemogenesis without IDH mutation. Using whole RNA sequencing of bone marrow cells in iron-overloaded mice, we observed that the enzymes, phosphoglucomutase 1, glycogen debranching enzyme, and isocitrate dehydrogenase 1 (Idh1), which are involved in glycogen and glucose metabolism, were increased. Digital PCR further showed that Idh1 and Aco1, enzymes involved in the TCA cycle, were also elevated. Additionally, enzymatic activities of TCA cycle and methylated DNA were increased. Iron chelation reversed these phenomena. In conclusion, iron activation of glucose metabolism causes an increase of 2-HG and DNA methylation.

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Correspondence to Hiroki Tanaka.

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This work was supported in part by a Grant-in-Aid for Scientific Research <KAKENHI> and Health and Labor Sciences Research Grant. The Department of Clinical Gastroenterology is endowed by Kyorin Phamaceutical Co., Ltd. (Tokyo, Japan), Sapporo Higashi Tokushukai Hospital (Sapporo, Japan), Asahi Kasei Medical Co., Ltd. (Tokyo, Japan), and Novartis Pharmaceuticals Japan Co., Ltd. (Tokyo, Japan). All of our projects involving iron metabolism are performed in collaboration with Novartis Pharmaceuticals Japan Co., Ltd. and Chugai Pharmaceuticals Japan Co., Ltd. (Tokyo, Japan). The authors would like to thank Mr. Hiroaki Akutsu (Center for Advanced Research and Education, Asahikawa Medical University, Hokkaido, Japan) for the technical assistance during GC–MS analysis. The original version of this manuscript have been published in Hokkaido Igakuzasshi [89 (2): 125-131, 2014] written in Japanese. Upon the official approval of Hokkaido Igakuzasshi, the English version of manuscript was re-submitted to this journal.

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Yamamoto, M., Tanaka, H., Toki, Y. et al. Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase. Int J Hematol 104, 491–501 (2016). https://doi.org/10.1007/s12185-016-2054-7

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  • DOI: https://doi.org/10.1007/s12185-016-2054-7

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