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Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase 山本, 昌代 ヤマモト, マサヨ 田中, 宏樹 タナカ, ヒロキ 土岐, 康通 トキ, ヤスミチ 畑山, 真弓 ハタヤマ, マユミ 伊藤, 巧 イトウ, サトシ Addo, Lynda 進藤, 基博 シンドウ, モトヒロ 佐々木, 勝則 ササキ, カツノリ 生田, 克哉 イクタ, カツヤ 大竹, 孝明 オオタケ, タカアキ 藤谷, 幹浩 フジヤ, ミキヒロ 鳥本, 悦宏 トリモト, ヨシヒロ 高後, 裕 コウゴ, ユタカ DNA methylation Iron overload Leukemia Myelodysplastic syndrome PMID：27380194 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. The final publication is available at Springer via http://dx.doi.org/10.1007/s12185-016-2054-7 text application/pdf 2016-10-01 eng journal article AM https://asahikawa-med.repo.nii.ac.jp/records/5795 10.1007/s12185-016-2054-7 0925-5710 International Journal of Hematology 104 4 491 501 https://asahikawa-med.repo.nii.ac.jp/record/5795/files/6755.pdf application/pdf 12.9 MB 2021-07-06