Establishment of iron chelation therapy to inhibit the development of MDS

• Project/Area Number: 24659466
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Sapporo Medical University
• Principal Investigator: KOBUNE Masayoshi 札幌医科大学, 医学部, 准教授 (90336389)
• Co-Investigator(Kenkyū-buntansha): KIKUCHI Shohei 札幌医科大学, 医学部, 助教 (80515792) ; IYAMA Satoshi 札幌医科大学, 医学部, 助教 (50398319) ; KATO Junji 札幌医科大学, 医学部, 教授 (20244345)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2014: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: MDS / 8-OHdG / 鉄キレート / 酸化的DNA損傷 / 鉄キレート剤 / 骨髄異形成症候群 / 幹細胞 / 白血病 / HPLC-ECD / 活性酸素 / 予後因子 / ゲノム / 腫瘍幹細胞

Outline of Final Research Achievements

Most MDS patients eventually require red RBC transfusions for anemia and consequently develop iron overload. Excess free iron in cells catalyzes generation of reactive oxygen species that cause oxidative stress, including oxidative DNA damage. However, it is uncertain how iron-mediated oxidative stress affects the pathophysiology of MDS. We analyzed 8-OHdG levels in peripheral blood mononuclear cells (PBMC) obtained from MDS patients before and after iron chelator,deferasirox, administration. We showed that the 8-OHdG levels in MDS patients were significantly higher than those in healthy volunteers and were positively correlated with SF and chromosomal abnormalities. Importantly, the 8-OHdG levels in PBMC of MDS patients significantly decreased after deferasirox administration, suggesting that iron chelation reduced oxidative DNA damage. Thus, excess iron could contribute to the pathophysiology of MDS and iron chelation therapy could improve the oxidative DNA damage in MDS patients.

Research Products

• [Journal Article] Narrowband ultraviolet B phototherapy ameliorates acute graft-versus-host disease by a mechanism involving in vivo expansion of CD4+CD25+Foxp3+ regulatory T cells． (2014)
  • Author(s): Iyama S，Murase K，Sato T，Hashimoto A，Tatekoshi A，Horiguchi H，Kamihara Y，Ono K，Kikuchi S，Takada K，Kawano Y，Hayashi T，Miyanishi K，Sato Y，Takimoto R，Kobune M，Mori S，Kato J，Yamashita T，Kato J．
  • Journal Title: Int J Hematol Volume: 99 Issue: 4 Pages: 471-476
  • DOI: 10.1007/s12185-014-1530-1
  • Peer Reviewed
• [Journal Article] A novel strategy inducing autophagic cell death in Burkitt’s lymphoma cells with anti-CD19-targeted liposomal rapamycin. (2014)
  • Author(s): Ono K, Sato T, Iyama S, Tatekoshi A, Hashimoto A, Kamihara Y, Horiguchi H, Kikuchi S, Kawano Y,Takada K, Hayashi T, Miyanishi K, Sato Y, Takimoto R, Kobune M, Kato J.
  • Journal Title: Blood Cancer J Volume: 7 Issue: 2 Pages: e180-e180
  • DOI: 10.1038/bcj.2014.2
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic significance of serum-ferritin level at diagnosis in myelodysplastic syndrome (2012)
  • Author(s): Kobune M, et al. 2^<nd>
  • Journal Title: Int J Hematol Volume: (In press) Issue: 5 Pages: 527-534
  • DOI: 10.1007/s12185-012-1048-3
  • NAID: 10030633185
  • Peer Reviewed
• [Journal Article] Improvement of iron-mediated oxidative DNA damage in patients with transfusion-dependent myelodysplastic syndrome by treatment with deferasirox. (2012)
  • Author(s): Kikuchi S, Kobune M, Iyama S, Sato T, Murase K, Kawano Y, Takada K, Ono K, Kaneko Y, Miyanishi K, Sato Y, Hayashi T, Takimoto R, Kato J.
  • Journal Title: Free Radic Biol Med Volume: 23(6) Issue: 4 Pages: 548-550
  • DOI: 10.1016/j.freeradbiomed.2012.06.006
  • Peer Reviewed
• [Presentation] Exosomes derived from AML/MDS cells could be involved in stromal dysfunction and bone marrow failure (2015)
  • Author(s): Jomen W, Horiguchi H, Kobune M, Kikuchi S, Murase K, Ibata S, Iyama S, Sato T, Kamihara Y, Miyanishi K, Sato Y, Hayashi T, Takimoto R, Kato J
  • Organizer: 2015 Highlights of ASH in Asia
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2015-02-28 – 2015-03-01
• [Presentation] Exosomes derived from AML/MDS cells could be involved in stromal dysfunction and bone marrow failure. (2014)
  • Author(s): Horiguchi H, Kobune M, Kikuchi S, Jomen W, Murase K, Ibata S, Iyama S, Sato T, Kamihara Y, Miyanishi K, Sato Y, Hayashi T, Takimoto R, Kato J.
  • Organizer: 56th ASH Annual Meeting and Exposition
  • Place of Presentation: San Francisco, U.S.A
  • Year and Date: 2014-12-06 – 2014-12-11
• [Presentation] 骨髄異形成症候群を増悪させる環境因子の解析 (2014)
  • Author(s): 小船雅義，堀口拓人，定免渉，菊地尚平，村瀬和幸，井山 諭，高田弘一，
  • Organizer: 第56回日本血液科学会秋季北海道地方会シンポジウム
  • Place of Presentation: 北海道大学（北海道, 札幌市）
  • Year and Date: 2014-09-27
• [Presentation] Iron chelation therapy improves oxidative DNA damage in hematopoietic cells derived from transfusion-dependent myelodysplastic syndrome
  • Author(s): Masayoshi Kobune
  • Organizer: International BioIron Society
  • Place of Presentation: ロンドン