title: Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase.
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.
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Gastrointestinal Immunology and Regenerative Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan. hiroki-t@asahikawa-med.ac.jp.|Department of Legal Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan. hiroki-t@asahikawa-med.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Toki
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Hatayama
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ito
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Lynda
authors.initials: L
authors.lastname: Addo
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Shindo
authors.affiliation: Department of Gastrointestinal Immunology and Regenerative Medicine, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa, Hokkaido, 078-8510, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Sasaki
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Ikuta
authors.affiliation: International University of Health and Welfare Hospital, Nasu-shiobara, Tochigi, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ohtake
authors.affiliation: Division of Gastroenterology and Hematology/Oncology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan.
authors.forename: Mikihiro
authors.initials: M
authors.lastname: Fujiya
authors.affiliation: Oncology Center, Asahikawa Medical University Hospital, Asahikawa, Hokkaido, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Torimoto
authors.affiliation: International University of Health and Welfare Hospital, Nasu-shiobara, Tochigi, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kohgo
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D063646:Carcinogenesis / Q000139:chemically induced; D019175:DNA Methylation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D005977:Glutarates / Q000097:blood; D007501:Iron / Q000494:pharmacology*; D035941:Iron Regulatory Protein 1 / Q000187:drug effects / Q000378:metabolism*; D007521:Isocitrate Dehydrogenase / Q000187:drug effects / Q000378:metabolism*; D051379:Mice
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; D007501:Iron; D007521:Isocitrate Dehydrogenase; D035941:Iron Regulatory Protein 1; D005947:Glucose
keywords: DNA methylation; Iron overload; Leukemia; Myelodysplastic syndrome