Generation and analysis of in vitro, in vivo model of sideroblastic anemia

• Project/Area Number: 26293225
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Tohoku University
• Principal Investigator: Harigae Hideo 東北大学, 医学(系)研究科(研究院), 教授 (50302146)
• Co-Investigator(Renkei-kenkyūsha): KAWAMATA Shin 公益財団法人先端医療振興財団, 副事業統括 (00360842) ; FUJIWARA Tohru 東北大学, 大学病院, 講師 (60333796)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2016: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 内科学 / 内科

Outline of Final Research Achievements

Sideroblastic anemia is characterized by anemia with ring sideroblasts in the bone marrow. In order to develop a novel therapy for sideroblastic anemia, iPS cells were established from a patient of X-linked sideroblastic anemia (XLSA), which is caused by mutations of 5-aminolevulinate synthase (ALAS2) gene. The expression profiling of erythroblasts derived from XLSA iPS cells showed that the expression levels of globins and erythroid-specific transcription factors were decreased compared to those derived from control iPS cells. When XLSA derived iPS cells were co-cultured with stromal cells; aberrant mitochondrial iron deposition was detected by prussian blue staining and electron microscope analysis. In addition, XLSA model mouse has been generated by introducing mutations to the enhancer lesion of ALAS2 gene by CRISPR/CAS9 system. Mutant mice were anemic, and the expression level of ALAS2 of bone marrow was decreased. Iron metabolism and erythropoiesis are under investigation.

Research Products

• [Journal Article] Forced FOG1 expression in erythroleukemia cells: Induction of erythroid genes and repression of myelo-lymphoid transcription factor PU.1 (2017)
  • Author(s): Fujiwara T, Sasaki K, Saito K, Hatta S, Ichikawa S, Kobayashi M, Okitsu Y, Fukuhara N, Onishi Y, Harigae H.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 485 Pages: 380-387
  • DOI: 10.1016/j.bbrc.2017.02.068
  • Peer Reviewed
• [Journal Article] Impact of TET2 deficiency on iron metabolism in erythroblasts (2017)
  • Author(s): Inokura K, Fujiwara T, Saito K, Iino T, Hatta S, Okitsu Y, Fukuhara N, Onishi Y, Ishizawa K, Shimoda K, Harigae H
  • Journal Title: Experimental Hematology Volume: - Pages: 56-67
  • DOI: 10.1016/j.exphem.2017.01.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical Utility of next-generation sequencing for inherited bone marrow failure syndromes (2017)
  • Author(s): Muramatsu H, Okuno Y, Yoshida K, Shiraishi Y, Doisaki S, Narita A, Sakaguchi H, Kawashima N, Wang X, Xu Y, Chiba K, Tanaka H, Hama A, Sanada M, Takahashi Y, Kanno H, Yamaguchi H, Ohga S, Manabe A, Harigae H, Kunishima S, Ishii E, Kobayashi M, Koike K, Watanabe K, Ito E, Takata M, Yabe M, Ogawa S, Miyano S, Kojima S.
  • Journal Title: Genetics in Medicine Volume: - Pages: 796-802
  • DOI: 10.1038/gim.2016.197
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Iron-heme-Bach1 axis is involved in erythroblast adaptation to iron deficiency. (2017)
  • Author(s): Kobayashi M, Kato H, Hada H, Itoh-Nakadai A, Fujiwara T, Muto A, Inoguchi Y, Ichiyanagi K, Hojo W, Tomosugi N, Sasaki H, Harigae H, Igarashi K.
  • Journal Title: Haematologica. Volume: 102 Pages: 454-465
  • DOI: 10.3324/haematol.2016.151043
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a novel putative mitochondrial protein FAM210B associated with erythroid differentiation. (2016)
  • Author(s): Kondo A, Fujiwara T, Okitsu Y, Fukuhara N, Onishi Y, Nakamura Y, Sawada K, Harigae H.
  • Journal Title: International Journal of Hematology Volume: 103 Pages: 387-395
  • DOI: 10.1007/s12185-016-1968-4
  • Peer Reviewed
• [Presentation] Identification of a novel mitochondorial protein FAM210B associated with erythroid differentiation (2016)
  • Author(s): 近藤愛子、藤原亨、沖津庸子、福原規子、大西康、中村幸夫、澤田賢一、張替秀郎
  • Organizer: 日本血液学会
  • Place of Presentation: パシフィコ横浜・横浜市
• [Presentation] Impact of TET2 on iron metabolism in erythroblasts:A potential link to ring sidero formation (2016)
  • Author(s): 斎藤慧、猪倉恭子、藤原亨、八田俊介、沖津庸子、福原規子、大西康、石澤賢一、下田和哉、張替秀郎
  • Organizer: 日本血液学会
  • Place of Presentation: パシフィコ横浜・横浜市
• [Presentation] 腸管上皮細胞モデルにおけるALAの代謝 (2016)
  • Author(s): 斎藤慧、藤原亨、田中徹、張替秀郎
  • Organizer: 日本鉄バイオサイエンス学会
  • Place of Presentation: 名古屋大学豊田講堂・名古屋市
• [Presentation] Clinical and genetic characteristics of sideroblastic anemia (2016)
  • Author(s): 張替秀郎
  • Organizer: the 14th China National Congress of Hematology
  • Place of Presentation: suzho jinji lake international convention center 上海・中国
  • Int'l Joint Research / Invited
• [Presentation] Generation of Induced Pluripotent Stem Cell-Derived Erythroblasts from a Patient with X-Linked Sideroblastic Anemia (2016)
  • Author(s): Shunsuke Hatta,Tohru Fujiwara, Takako Yamamoto, Mayumi Kamata, Yoshiko Tamai, Yukio Nakamura, Shin Kawamata, Hideo Harigae
  • Organizer: 58th Annual Meeting of American Sciety of Hematology
  • Place of Presentation: SanDiego convention center サンディエゴ・米国
  • Int'l Joint Research
• [Presentation] 遺伝性鉄芽球性貧血の疫学と分子病態 (2015)
  • Author(s): 藤原亨、張替秀郎
  • Organizer: 第39回日本鉄バイオサイエンス学会学術集会
  • Place of Presentation: 岡山コンベンションセンター(岡山市）
  • Year and Date: 2015-08-29
  • Invited
• [Presentation] Exploring potential usefulness of 5-aminolevulinic acid for X-linked sideroblastic anemia (2014)
  • Author(s): Fujiwara T, Okamoto K, Niikuni R, Takahashi K, Okitsu Y, Fukuhara N, Onishi Y, Ishizawa K, Ichinohasama R, Nakamura Y, Nakajima M, Tanaka T, Harigae H
  • Organizer: 第56回アメリカ血液学会
  • Place of Presentation: サンフランシスコ(米国)
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Impact of TET2 deficiency on iron metabolism in erythropoiesis:a potential link to ring sideroblast formation (2014)
  • Author(s): Inokura K, Fujiwara T, Okitsu Y, Fukuhara N, Onishi Y, Ishizawa K, Shimoda K, Harigae H
  • Organizer: 第56回アメリカ血液学会
  • Place of Presentation: サンフランシスコ(米国)
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] Exploring the potential usefulness of 5-aminolevulinic acid (ALA) for sideroblastic anemia (2014)
  • Author(s): Nikuni R, Fujiwara T, Okitsu Y, Fukuhara N, Onishi Y, Ishizawa K, Ichinohasama R, Tanaka T, Harigae H
  • Organizer: 第76回日本血液学会
  • Place of Presentation: 大阪国際会議場(大阪府)
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] 鉄芽球性貧血に対するALAの有用性の基礎的検討 (2014)
  • Author(s): 藤原亨、新國僚祐、田中徹、張替秀郎
  • 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(仙台市)
  • Year and Date: 2014-09-06 – 2014-09-07
• [Presentation] TET2遺伝子の鉄芽球性貧血発症への関与 (2014)
  • Author(s): 猪倉恭子、藤原亨、下田和哉、張替秀郎
  • 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(仙台市)
  • Year and Date: 2014-09-06 – 2014-09-07