Investigation for the inhibition of erythropoiesis by non-transferrin-bound iron and its recovery by iron chelation

• Project/Area Number: 24591377
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Asahikawa Medical College
• Principal Investigator: IKUTA Katsuya 旭川医科大学, 医学部, 講師 (00396376)
• Co-Investigator(Kenkyū-buntansha): SASAKI Katsunori 旭川医科大学, 医学部, 特任教授 (60336394) ; ITO Satoshi 旭川医科大学, 医学部, 特任助教 (80548686)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 非トランスフェリン結合鉄 / 鉄過剰症 / 造血障害 / 糖代謝異常 / 糖代謝

Outline of Final Research Achievements

The present study was performed to elucidate the machanisms for the inhibition of hematopoiesis by iron overload and its recovery by iron chelation. Mice were administrated with iron dextran, and these mice showed iron deposition in bone marrow, increased serum iron and serum ferritin, and non-transferrin-bound iron (NTBI). Iron chelation therapy was also performed for those iron-overloaded mice. Comparison of gene expressions between those models indicated that the expressions of the genes related to glucose metabolism were changed responding to iron status. Among them, the expessions of aconitase and isocitrate dehedrogenase, those were important in TCA cycle, increased in iron overload and improved by iron chelation. 2-hydroxyglutarate (2-HG)and DNA methylation were also increased. Combinding our data, iron overload can increase DNA methylation via increase of 2-HG even without any mutation in IDH gene, finally resulting in the inhibition of hematopoiesis or leukemic change.

Research Products

• [Journal Article] Two novel potential markers for iron metabolism: hepcidin and non-transferrin-bound iron (NTBI) (2015)
  • Author(s): 生田克哉
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 2 Pages: 194-203
  • DOI: 10.11406/rinketsu.56.194
  • NAID: 130004920708
  • ISSN: 0485-1439, 1882-0824
• [Journal Article] 鉄代謝バイオマーカーの現状と開発動向（特集：鉄代謝制御機構と鉄過剰症）． (2015)
  • Author(s): 畑山真弓、生田克哉
  • Journal Title: 血液内科 Volume: 70 Pages: 315-320
  • NAID: 40020446653
• [Journal Article] Non-transferrin-bound iron assay system utilizing a conventional automated analyzer. (2014)
  • Author(s): Ito S, Ikuta K, Kato D, Shibusa K, Niizeki N, Tanaka H, Addo L, Toki Y, Hatayama M, Inamura J, Shindo M, Sasaki K, Iizuka N, Fujiya M, Torimoto Y, Kohgo Y.
  • Journal Title: Clinica Chimica Acta Volume: 437 Pages: 129-135
  • DOI: 10.1016/j.cca.2014.07.013
  • NAID: 120005476958
  • Peer Reviewed
• [Journal Article] Up-regulation of iron regulatory hormone hepcidin by interferon α. (2014)
  • Author(s): Ichiki K, Ikuta K, Addo L, Tanaka H, Sasaki Y, Shimonaka Y, Sasaki K, Ito S, Shindo M, Ohtake T, Fujiya M, Torimoto Y, Kohgo Y.
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 29 Issue: 2 Pages: 387-394
  • DOI: 10.1111/jgh.12348
  • Peer Reviewed
• [Journal Article] Hyperferritinemia after adult allogeneic hematopoietic cell transplantation: quantification of iron burden by determining non-transferrin-bound iron. (2013)
  • Author(s): Tatsunori Goto, Katsuya Ikuta, Yoshihiro Inamoto, Sonoko Kamoshita, Emi Yokohata, Daisuke Koyama, Koichi Onodera, Aika Seto, Keisuke Watanabe, Nobuhiko Imahashi, Shokichi Tsukamoto, Yukiyasu Ozaw, Katsunori Sasaki, Masafumi Ito, Yutaka Kohgo, Koichi Miyamura
  • Journal Title: Int J Hematol. Volume: 97 Issue: 1 Pages: 125-134
  • DOI: 10.1007/s12185-012-1252-1
  • NAID: 10031144644
  • Peer Reviewed
• [Journal Article] Iron overload signature in chrysotile-induced malignant mesothelioma. (2012)
  • Author(s): Jiang L, Akatsuka S, Nagai H, Chew SH, Ohara H, Okazaki Y, Yamashita Y, Yoshikawa Y, Yasui H, Ikuta K, Sasaki K, Kohgo Y, Hirano S, Shinohara Y, Kohyama N, Takahashi T, Toyokuni S.
  • Journal Title: J Pathol Volume: 228 Issue: 3 Pages: 366-77
  • DOI: 10.1002/path.4075
  • Peer Reviewed
• [Journal Article] 経口鉄キレート剤が血清鉄・不飽和鉄結合能測定系に与える影響． (2012)
  • Author(s): 伊藤 巧、生田克哉．
  • Journal Title: Medical Technology Volume: 40 Pages: 1054-1057
• [Journal Article] MDSにおけるdeferasiroxの臨床効果． (2012)
  • Author(s): 生田克哉．
  • Journal Title: 血液内科 Volume: 65 Pages: 736-742
  • NAID: 40019515793
• [Journal Article] 鉄キレート剤が血清鉄・UIBCに及ぼす影響． (2012)
  • Author(s): 生田克哉．
  • Journal Title: 臨床検査 Volume: 56 Pages: 1115-1119
• [Journal Article] 非トランスフェリン結合鉄． (2012)
  • Author(s): 佐々木勝則、生田克哉、鳥本悦宏、高後 裕．
  • Journal Title: 臨床検査 Volume: 56 Pages: 1070-1082
• [Presentation] Functional validation and clinical significance of a newly established non-transferrin-iron (NTBI) assay system utilizing conventional autometad analyzer. (2014)
  • Author(s): Satoshi Ito, Lynda Addo, Daisuke Kato, Mayumi Hatayama, Yasumichi Toki, Hiroki Tanaka, Motohiro Shindo, Naomi Iizuka, Katsuya Ikuta, Katsunori Sasaki, Yoshihiro Torimoto, Yutaka Kohgo.
  • Organizer: The 4th Asia Pacific Iron Academy Conference.
  • Place of Presentation: Mandarin Oriental Hotel, Jakarta, Indonesia
  • Year and Date: 2014-11-01 – 2014-11-02
• [Presentation] Aberrant glucose metabolism by iron overload causes excessive DNA methylation in bone marrow cells. (2014)
  • Author(s): Masayo Yamamoto, Hiroki Tanaka, Katsunori Sasaki, Satoshi Ito, Motohiro Shindo, Katsuya Ikuta, Kentaro Moriichi, Takaaki Ohtake, Mikihiro Fujiya, Yoshihiro Torimoto, Yutaka Kohgo.
  • Organizer: The 4th Asia Pacific Iron Academy Conference.
  • Place of Presentation: Mandarin Oriental Hotel, Jakarta, Indonesia
  • Year and Date: 2014-11-01 – 2014-11-02
• [Presentation] Aberrant glucose metabolism by iron overload causes excessive DNA methylation in bone marrow cells. (2014)
  • Author(s): Masayo Yamamoto, Hiroki Tanaka, Yasumichi Toki, Mayumi Hatayama, Satoshi Ito, Junki Inamura, Motohiro Shindo, Katsunori Sasaki, Katsuya Ikuta, Takaaki Ohtake, Mikihiro Fujiya, Yoshihiro Torimoto, Yutaka Kohgo.
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-10-31
• [Presentation] Iron-overload alters lipid metabolism and activates Ras signaling in mouse liver being independent of oxidative stress． (2014)
  • Author(s): 田中宏樹、アドリンダ、山本昌代、土岐康通、澤田康司、生田克哉、佐々木勝則、大竹孝明、鳥本悦宏、藤谷幹浩、高後 裕．
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-26
• [Presentation] マウス骨髄細胞における鉄過剰による糖代謝異常とDNAメチル化の亢進． (2014)
  • Author(s): 山本昌代、田中宏樹、土岐康通、畑山真弓、伊藤 巧、進藤基博、佐々木勝則、生田克哉、大竹孝明、藤谷幹浩、鳥本悦宏、高後 裕．
  • Organizer: 第38回日本鉄バイオサイエンス学会学術集会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2014-09-06
• [Presentation] Iron-induced epigenetic abnormality of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase without gene mutation: analysis by high throughput sequencer and GC-MS. (2014)
  • Author(s): Yamamoto M, Tanaka H, Toki Y, Hatayama M, Ito S, Inamura J, Shindo M, Ikuta K, Sasaki K, Ohtake T, Fujiya M, Torimoto Y, Kohgo Y.
  • Organizer: 19th Congress of European Hematology Association
  • Place of Presentation: MiCo Milano Congressi in Milan, Italy
  • Year and Date: 2014-06-14
• [Presentation] 自動分析装置による血清中非トランスフェリン結合鉄（NTBI）測定． (2014)
  • Author(s): 畑山真弓、生田克哉、渋佐琴恵、進藤基博、高後 裕、新関紀康、紀野修一．
  • Organizer: 第62回日本輸血・細胞治療学会総会
  • Place of Presentation: 奈良県文化会館
  • Year and Date: 2014-05-16
• [Presentation] The three isoforms fo human hepcidin: Measurement and assessment of their processing in health and chronic kidney disease using LC-tandem MS. (2012)
  • Author(s): S. Ito, K. Ikuta, L. Addo, M. Shindo, Y. Torimoto, Y. Kohgo.
  • Organizer: The 3rd Asia Pacific Iron Academy Conference.
  • Place of Presentation: The Gland Hotel, Taipei, Taiwan.
• [Presentation] Increased Expression Of NGF In Hepatocytes Is An Early Event In Iron Overloaded Mouse By Transcriptome Analysis.
  • Author(s): Masayo Yamamoto, Hiroki Tanaka, Lynda Addo, Satoshi Ito, Motohiro Shindo, Katsuya Ikuta, Katsunori Sasaki, Takaaki Ohtake, Mikihiro Fujiya, Yoshihiro Torimoto, Yutaka Kohgo.
  • Organizer: ASH 2013 (Annual Meeting of American Society of Hematology)
  • Place of Presentation: Ernest N. Morial Convention Center, New Orleans, LA, U.S.A.
• [Presentation] Functional Validation and Clinical Significance Of a Newly Established Non-Transferrin-Bound Iron (NTBI) Assay System Utilizing Conventional Automated Analyzer.
  • Author(s): Satoshi Ito, Katsuya Ikuta, Lynda Addo, Mayumi Hatayama, Yasumichi Toki, Hiroki Tanaka, Junki Inamura, Motohiro Shindo, Yoshihiro Torimoto, Yutaka Kohgo.
  • Organizer: ASH 2013 (Annual Meeting of American Society of Hematology)
  • Place of Presentation: Ernest N. Morial Convention Center, New Orleans, LA, U.S.A.
• [Presentation] Novel quantification system of non-transferrin-bound iron (NTBI) utilizing automatic analyzer.
  • Author(s): K. Ikuta, S. Ito, L. Addo, M. Hatayama, Y. Toki, J. Inamura, M. Shindo, H. Tanaka, K. Sasaki, Y. Torimoto, Y. Kohgo.
  • Organizer: Fifth Congress of the International BioIron Society (IBIS), Biennial World Meeting (BioIron 2013 )
  • Place of Presentation: University College London, London, United Kingdom
• [Presentation] Changes of the expressions of the genes involved in iron metabolism by the iron chelation using deferasirox in the iron overloaded mouse model.
  • Author(s): Y. Toki, K. Ikuta, L. Addo, M. Hatayama, S. Ito, J. Inamura, M. Shindo, H. Tanaka, K. Sasaki, Y. Torimoto, Y. Kohgo.
  • Organizer: Fifth Congress of the International BioIron Society (IBIS), Biennial World Meeting (BioIron 2013 )
  • Place of Presentation: University College London, London, United Kingdom
• [Presentation] 自動分析装置による血清中非トランスフェリン結合鉄（NTBI）測定．
  • Author(s): 生田克哉、伊藤 巧、新関紀康、紀野修一、高後 裕．
  • Organizer: 第60回日本臨床検査医学会学術集会
  • Place of Presentation: 神戸国際会議場
• [Presentation] Iron metabolism and its novel markers.
  • Author(s): 生田克哉
  • Organizer: 第75回日本血液学会学術集会（シンポジウム）
  • Place of Presentation: さっぽろ芸文館、札幌
• [Presentation] Nobel quantification system for non-transferrin-bound iron utilizing conventional automated analyzer.
  • Author(s): 稲村純季、生田克哉、加藤大介、飯塚直美、畑山真弓、土岐康通、伊藤 巧、田中宏樹、佐々木勝則、進藤基博、鳥本悦宏、高後 裕．
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: さっぽろ芸文館、札幌
• [Presentation] Nobel Non-Transferrin-Bound Iron (NTBI) Measuring System Utilizing Automatic Analyzer.
  • Author(s): S. Ito, K. Ikuta, K. Sasaki, M. Shindo, Y. Torimoto, Y. Kohgo.
  • Organizer: ASH 2012 (Annual Meeting of American Society of Hematology)
  • Place of Presentation: Georgia World Congress Center, Atlanta, U.S.A.
• [Presentation] 血清中非トランスフェリン結合鉄（NTBI）定量法の確立
  • Author(s): 生田克哉、進藤基博、新関紀康、友田 豊、紀野修一、伊藤喜久、高後 裕．
  • Organizer: 第59回日本臨床検査医学会学術集会
  • Place of Presentation: 国立京都国際会館
• [Presentation] 自動分析装置によるNTBI測定試薬の開発
  • Author(s): 加藤大介、飯塚直美、生田克哉、佐々木勝則、高後 裕．
  • Organizer: 第36回日本鉄バイオサイエンス学会学術集会
  • Place of Presentation: 京王プラザホテル札幌
• [Book] プリンシプル血液疾患の臨床：新戦略による貧血治療（担当部分：鉄代謝のバイオマーカー） (2014)
  • Author(s): 生田克哉
  • Total Pages: 304
  • Publisher: 中山書店
• [Book] EBM血液疾患の治療2013－2014（担当部分：鉄代謝と輸血後鉄過剰症に対する治療方針．（IV．支持療法・輸血）） (2012)
  • Author(s): 生田克哉、高後 裕．
  • Total Pages: 590
  • Publisher: 中外医学社
• [Book] 慢性肝疾患における鉄毒性と除鉄治療～C型慢性肝炎を中心に～（担当部分：鉄の体内動態（第1部：基礎の部）） (2012)
  • Author(s): 生田克哉、高後 裕．
  • Total Pages: 208
  • Publisher: 医薬ジャーナル社