Elucidation of the role of GATA-2 in regulating functional linkage between hematopoietic stem cells and bone marrow microenvironment

• Project/Area Number: 21K08385
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Iwate Medical University (2023-2024); Tohoku University (2021-2022)
• Principal Investigator: FUJIWARA TOHRU 岩手医科大学, 医学部, 准教授 (60333796)
• Project Period (FY): 2021-04-01 – 2025-03-31
• Project Status: Completed (Fiscal Year 2024)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: GATA-2 / 造血微小環境 / 造血幹細胞

Outline of Research at the Start

造血不全症の代表疾患の一つである再生不良性貧血は、骨髄の造血幹細胞の減少と脂肪髄を特徴とする難治性疾患の一つである。これまでに申請者らのグループは、造血幹細胞と造血幹細胞を支持する造血微小環境を構成する間葉系幹細胞の両者における転写因子GATA-2の発現低下が、造血細胞の減少と脂肪髄という二つの異常形質と深く関わることを見出してきた。さらに間葉系幹細胞におけるGATA-2の発現低下により造血支持能が低下する点も明らかとした。しかしながら、造血幹細胞の質的異常が造血微小環境に与える影響については不明である。本研究ではこの点を明らかとすることを目的とした。

Outline of Final Research Achievements

Aplastic anemia is characterized by decreased frequency of hematopoietic stem cells (HSCs) and fatty marrow replacement. We have demonstrated that decreased GATA-2 expression in HSCs and bone marrow mesenchymal stem cells (BM-MSCs) would contribute to decreased frequency of HSCs and fatty marrow changes, respectively. However, it has remained unknown regarding the potential direct effect of qualitative abnormality of HSCs due to GATA-2 downregulation on the function of BM-MSCs. We conducted shRNA-mediated knockdown of GATA-2 based on cord blood-derived CD34-positive HSCs, and subsequently conducted detailed analyses, including comprehensive expression profiling.

Academic Significance and Societal Importance of the Research Achievements

今回の研究成果は、今後ex vivoあるいはin vivoにおける造血幹細胞修飾等を通じた造血不全症の新規治療法の開発への研究展開が期待されるのみならず、造血幹細胞と造血微小環境の機能的連関の生理学的機構及びその機能的連関におけるGATA-2の意義に関する理解が深まることが期待される。

Research Products

• [Journal Article] Pyridoxine: beyond a cofactor of ALAS (2024)
  • Author(s): Fujiwara Tohru、Harigae Hideo
  • Journal Title: Blood Volume: 144 Issue: 13 Pages: 1358-1359
  • DOI: 10.1182/blood.2024025575
  • Peer Reviewed
• [Journal Article] Flavonifractor plautii Bacteremia With Generalized Peritonitis: A Case Report and Literature Review (2024)
  • Author(s): Saito Shogo、Baba Shigeaki、Nikai Haruka、Fujisawa Ryosuke、Fujiwara Tohru
  • Journal Title: Cureus Volume: 16
  • DOI: 10.7759/cureus.63890
  • Peer Reviewed
• [Journal Article] von Willebrand factor Ristocetin co-factor activity to von Willebrand factor antigen level ratio for diagnosis of acquired von Willebrand syndrome caused by aortic stenosis (2024)
  • Author(s): Okubo N, Sugawara S, Fujiwara T, Sakatsume K, Doman T, Yamashita M, Goto K, Tateishi M, Suzuki M, Shirakawa R, Eura Y, Kokame K, Hayakawa M, Matsumoto M, Kawate Y, Miura M, Takiguchi H, Soga Y, Shirai S, Ando K, Arai Y, Nakayoshi T, Fukumoto Y, Takahama H, Yasuda S, Tamura T, Watanabe S, Kimura T, et al
  • Journal Title: Research and Practice in Thrombosis and Haemostasis Volume: 8 Issue: 1 Pages: 102284-102284
  • DOI: 10.1016/j.rpth.2023.102284
  • Peer Reviewed / Open Access
• [Journal Article] BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state (2023)
  • Author(s): Xiao Muran、、、、Yokoyama Akihiko、、、、、Inoue Daichi
  • Journal Title: Nature Communications Volume: 14 Issue: 1 Pages: 1-22
  • DOI: 10.1038/s41467-023-44081-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heme-dependent induction of mitophagy program during differentiation of murine erythroid cells (2023)
  • Author(s): Ikeda Masatoshi、Kato Hiroki、Shima Hiroki、Matsumoto Mitsuyo、Furukawa Eijiro、Yan Yan、Liao Ruiqi、Xu Jian、Muto Akihiko、Fujiwara Tohru、Harigae Hideo、Bresnick Emery H.、Igarashi Kazuhiko
  • Journal Title: Experimental Hematology Volume: 118 Pages: 21-30
  • DOI: 10.1016/j.exphem.2022.11.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Elucidation of the Role of FAM210B in Mitochondrial Metabolism and Erythropoiesis (2022)
  • Author(s): Suzuki Chie、Fujiwara Tohru、Shima Hiroki、Ono Koya、Saito Kei、Kato Hiroki、Onodera Koichi、Ichikawa Satoshi、Fukuhara Noriko、Onishi Yasushi、Yokoyama Hisayuki、Nakamura Yukio、Igarashi Kazuhiko、Harigae Hideo
  • Journal Title: Molecular and Cellular Biology Volume: 42 Issue: 12
  • DOI: 10.1128/mcb.00143-22
  • Peer Reviewed
• [Journal Article] HSPA9 frameshift and loss‐of‐function mutations in a patient manifesting syndromic sideroblastic anemia and congenital anomalies (2022)
  • Author(s): Watanabe Atsuko、Fujiwara Tohru、Ohta Atsuhiko、Shimizu Yuki、Tanaka Ryuhei
  • Journal Title: Pediatric Blood & Cancer Volume: 70 Issue: 3
  • DOI: 10.1002/pbc.29971
  • Peer Reviewed
• [Journal Article] Exploring the mechanistic link between SF3B1 mutation and ring sideroblast formation in myelodysplastic syndrome (2022)
  • Author(s): Ochi Tetsuro、Fujiwara Tohru、Ono Koya、Suzuki Chie、Nikaido Maika、Inoue Daichi、Kato Hiroki、Onodera Koichi、Ichikawa Satoshi、Fukuhara Noriko、Onishi Yasushi、Yokoyama Hisayuki、Nakamura Yukio、Harigae Hideo
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 14562-14562
  • DOI: 10.1038/s41598-022-18921-2
  • Peer Reviewed / Open Access
• [Journal Article] Congenital sideroblastic anemia model due to ALAS2 mutation is susceptible to ferroptosis (2022)
  • Author(s): Ono Koya、Fujiwara Tohru、Saito Kei、Nishizawa Hironari、Takahashi Noriyuki、Suzuki Chie、Ochi Tetsuro、Kato Hiroki、Ishii Yusho、Onodera Koichi、Ichikawa Satoshi、Fukuhara Noriko、Onishi Yasushi、Yokoyama Hisayuki、Yamada Rie、Nakamura Yukio、Igarashi Kazuhiko、Harigae Hideo
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 9024-9024
  • DOI: 10.1038/s41598-022-12940-9
  • Peer Reviewed / Open Access
• [Journal Article] Unrelated cord blood transplantation for adult-onset EBV-associated T-cell and NK-cell lymphoproliferative disorders (2022)
  • Author(s): Onishi Yasushi、Onodera Koichi、Fukuhara Noriko、Kato Hiroki、Ichikawa Satoshi、Fujiwara Tohru、Yokoyama Hisayuki、Yamada-Fujiwara Minami、Harigae Hideo
  • Journal Title: International Journal of Hematology Volume: - Issue: 6 Pages: 873-881
  • DOI: 10.1007/s12185-022-03313-z
  • Peer Reviewed
• [Journal Article] Salvage Cord Blood Transplantation for Sustained Remission of Acute Megakaryoblastic Leukemia That Relapsed Early after Myeloablative Transplantation (2021)
  • Author(s): Ichikawa Satoshi、Fujiwara Tohru、Saito Kei、Sakurai Kazuki、Inokura Kyoko、Fukuhara Noriko、Yokoyama Hisayuki、Onodera Koichi、Onishi Yasushi、Kameoka Junichi、Harigae Hideo
  • Journal Title: Internal Medicine Volume: 60 Issue: 18 Pages: 3015-3019
  • DOI: 10.2169/internalmedicine.6796-20
  • NAID: 130008088286
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-09-15
  • Peer Reviewed / Open Access
• [Journal Article] Targeting stanniocalcin‐1‐expressing tumor cells elicits efficient antitumor effects in a mouse model of human lung cancer (2021)
  • Author(s): Abe Kotaro、Kanehira Masahiko、Ohkouchi Shinya、Kumata Sakiko、Suzuki Yamato、Oishi Hisashi、Noda Masafumi、Sakurada Akira、Miyauchi Eisaku、Fujiwara Tohru、Harigae Hideo、Okada Yoshinori
  • Journal Title: Cancer Medicine Volume: 10 Issue: 9 Pages: 3085-3100
  • DOI: 10.1002/cam4.3852
  • Peer Reviewed / Open Access
• [Presentation] 鉄芽球性貧血の病態 (2024)
  • Author(s): 藤原亨
  • Organizer: 第86回日本血液学会学術集会
  • Invited
• [Presentation] 造血幹前駆細胞の生体内造血におけるヘム合成の役割 (2024)
  • Author(s): 加藤浩貴, 燕艶, 櫻井一貴,藤原亨, 張替秀郎
  • Organizer: 第48回日本鉄バイオサイエンス学会学術集会
• [Presentation] 交換輸血を施行した抗Kg（Katagiri）による新生児溶血性疾患の一症例 (2024)
  • Author(s): 佐々木哲也, 伊藤正一, 荻山佳子, 髙橋蓮, 井上優花子, 佐野友美, 外川洋子, 後藤健治, 松尾悠, 阿部志津香, 土屋繁国, 髙清水奈央, 鳥谷由貴子, 外舘玄一郎, 松本敦, 坂口俊, 三浦邦彦, 高舘潤子, 伊藤薫樹, 藤原亨
  • Organizer: 第72回日本輸血・細胞治療学会学術総会
• [Presentation] 鉄代謝異常と貧血 (2023)
  • Author(s): 藤原 亨
  • Organizer: 第123回日本輸血・細胞治療学会 東北支部例会
• [Presentation] 鉄代謝異常に伴う貧血の病態と検査への応用 (2023)
  • Author(s): 藤原 亨
  • Organizer: 第70回日本臨床検査医学会学術集会
• [Presentation] 赤血球ヘム合成系とその異常 (2023)
  • Author(s): 藤原 亨
  • Organizer: 第47回日本鉄バイオサイエンス学会学術集会
• [Presentation] Mitochondrial metabolism and erythroid differentiation (2023)
  • Author(s): Fujiwara T, Suzuki C, Harigae H
  • Organizer: 第85回日本血液学会学術集会
• [Presentation] Comparison of VWF:RCo/VWF:Ag ratios with the VWF large multimer indices in patients with aortic stenosis (2023)
  • Author(s): Horiuchi H, Okubo N, Sugawara S, Fujiwara T, Eura Y, Kokame K, Hayakawa M, Matsumoto M, Kawate Y, Fujimaki S
  • Organizer: The International Society on Thrombosis and Haemostasis 2023 Congress
• [Presentation] Roles for heme synthesis in the maintenance of hematopoietic stem and progenitor cells (2023)
  • Author(s): Yan Y, Kato H, Sano S, Furukawa E, Michimata D, Tanaka Y, Sakurai K, Onodera K, Ichikawa S, Fujiwara T, Onishi Y, Fukuhara N, Yokoyama H, Harigae H
  • Organizer: The 13th Japanese Society of Hematology International Meeting
• [Presentation] Transcription factor GATA2 is inevitable for the survival and proper differentiation of thymic multipotent progenitor cells by gene expression orchestration (2023)
  • Author(s): Sano S, Kato H, Yan Y, Furukawa E, Michimata D, Tanaka Y, Sakurai K, Onodera K, Ichikawa S, Fukuhara N, Onishi Y, Yokoyama H, Fujiwara T, Harigae H
  • Organizer: The 65th American Society of Hematology
• [Presentation] Roles for heme synthesis in the maintenance of hematopoietic stem and progenitor cells (2023)
  • Author(s): Yan Y, Kato H, Sano S, Furukawa E, Michimata D, Tanaka Y, Sakurai K, Onodera K, Ichikawa S, Fujiwara T, Onishi Y, Fukuhara N, Yokoyama H, Harigae H
  • Organizer: The 65th American Society of Hematology
• [Presentation] Hematopoietic stem/progenitor cell intrinsic SAM synthesis is required to prevent p53 pathway activation by maintaining DNA stability (2023)
  • Author(s): Furukawa E, Kato H, Sano S, Yan Y, Michimata D, Tanaka Y, Sakurai K, Onodera K, Ichikawa S, Fukuhara N, Onishi Y, Yokoyama H, Saegusa D, Fujiwara T, Igarashi K, Harigae H
  • Organizer: The 65th American Society of Hematology
• [Presentation] ヒト赤芽球細胞株を用いた造血性プロトポルフィリン症の病態解明 (2023)
  • Author(s): 二階堂舞香, 藤原亨, 鈴木千恵, 小野浩弥, 加藤浩貴, 小野寺晃一, 市川聡, 福原規子, 大西康, 横山寿行, 中村幸夫, 張替秀郎
  • Organizer: 第47回日本鉄バイオサイエンス学会学術集会
• [Presentation] Impact of FECH deficiency on ring sideroblast formation in erythroblasts (2022)
  • Author(s): Nikaido M, Fujiwara T, Suzuki C, Ono K, Kato H, Onodera K, Ichikawa S, Fukuhara N, Onishi Y, Yokoyama H, Nakamura Y, Harigae H
  • Organizer: 第84回日本血液学会
• [Presentation] Exploring the mechanistic link between SF3B1 mutation and ring sideroblast formation in MDS (2022)
  • Author(s): Ochi T, Fujiwara T, Ono K, Suzuki C, Inoue D, Kato H, Onodera K, Ichikawa S, Fukuhara N, Onishi Y, Yokoyama H, Nakamura Y, Harigae H
  • Organizer: 第84回日本血液学会
• [Presentation] Integration of erythroid differentiation and autophagy by iron-heme metabolism (2022)
  • Author(s): Igarashi K, Kato H, Ikeda M, Fujiwara T, Harigae H
  • Organizer: 第84回日本血液学会
  • Invited
• [Presentation] Altered transcription by GATA1 impairs autophagy and prevents ferroptosis in X-linked sideroblastic anemia (2022)
  • Author(s): Ono K, Fujiwara T, Shima H, Suzuki C, Takahashi N, Nishizawa H, Onodera K, Ichikawa S, Fukuhara N, Onishi Y, Hisayuki Y, Fujimaki S, Nakamura Y, Igarashi K, Harigae H
  • Organizer: 第64回米国血液学会
  • Int'l Joint Research
• [Presentation] Inhibition of S-Adenosylmethionine synthesis promotes erythropoiesis via epigenetic modifications. (2021)
  • Author(s): Kato H, Long NC, Ishii Y, Matsumoto M, Rhee C, Saigusa D, Funayama R, Okae H, Fujiwara T, Muto A, Harigae H, Scadden DT, Igarashi K.
  • Organizer: 第63回米国血液学会
  • Int'l Joint Research
• [Presentation] Monitoring CAR-T cells using flow cytometry: A feasibility study. (2021)
  • Author(s): Fujiwara T, Onishi Y, Niizuma H, Okubo N, Sugawara S, Moriya K, Ichikawa S, Irie M, Fukuhara N, Yokoyama H, Fujiwara M, Fujimaki S, Sasahara Y, Harigae H.
  • Organizer: 第12回日本血液学会国際シンポジウム
  • Int'l Joint Research
• [Presentation] FOG1-dependent transcriptional network involves glucose metabolic regulation of erythroid cells. (2021)
  • Author(s): Fujiwara T, Suzuki C, Ono K, Saito K, Kato H, Onodera K, Ichikawa S, Fukuhara N, Onishi Y, Yokoyama H, Harigae H.
  • Organizer: 第83回日本血液学会
• [Presentation] Elucidation of the role of FAM210B in mitochondrial metabolism in erythroblasts. (2021)
  • Author(s): Suzuki C, Fujiwara T, Shima H, Ono K, Saito K, Kato H, Onodera K, Ichikawa S, Fukuhara N, Onishi Y, Yokoyama H, Nakamura Y, Harigae H.
  • Organizer: 第83回日本血液学会
• [Presentation] Cellular models of X-linked sideroblastic anemia based on immortalized human erythroid progenitors. (2021)
  • Author(s): Ono K, Fujiwara T, Saito K, Suzuki C, Takahashi N, Kato H, Onodera K, Ichikawa S, Fukuhara N, Onishi Y, Yokoyama H, Nakamura Y, Harigae H.
  • Organizer: 第83回日本血液学会
• [Presentation] Methionine metabolism controls erythropoiesis by epigenetic regulation. (2021)
  • Author(s): Kato H, Long NC, Ishii Y, Matsumoto M, Mitsueda D, Funayama R, Okae H, Fujiwara T, Muto A, Nakayama K, Arima T, Scadden D, Igarashi K, Harigae H.
  • Organizer: 第83回日本血液学会