Regulation of normal and malignant hematopoiesis by protein glycosylation with O-GlcNAc

• Project/Area Number: 17K09909
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Yokohama City University
• Principal Investigator: NAKAJIMA HIDEAKI 横浜市立大学, 医学研究科, 教授 (30217723)
• Co-Investigator(Kenkyū-buntansha): 田村 智彦 横浜市立大学, 医学研究科, 教授 (50285144)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 造血幹細胞 / OGT / O-GlcNAc / ミトコンドリア / マイトファジー / O-GlcNAc修飾 / 血球分化 / 造血器腫瘍 / O結合型β-N-アセチルグルコサミン

Outline of Final Research Achievements

O-GlcNAc transferase (OGT) confers O-GlcNAc moiety to the serine/ threonine residue of the target proteins. O-GlcNAcylation plays a critical role for regulating protein function and epigenetic modification. We have preformed in-depth functional analysis of OGT in hematopoietic stem cells (HSCs) using Ogt-conditional knockout mice and found that OGT is crucial for HSC maintenance. OGT disruption in vivo led to decreased HSCs and impaired HSC function. Further analysis revealed that OGT is critical for quality control of mitochondria in HSCs through mitophagy regulation.

Academic Significance and Societal Importance of the Research Achievements

これまでO-GlcNAc化は細胞機能・成体恒常性維持の様々な局面で極めて重要な役割を果たしており、その異常は糖尿病などの代謝性疾患、アルツハイマー病などの変性疾患、さらには発癌や老化と密接に関係していることが知られていたが、HSCにおける役割は未解明であった。本研究はOGTがHSC維持において必須の役割を果たしていることを明らかにした世界初の報告であり、学術的意義は極めて高い。本研究はOGTやO-GlcNAc化の制御によりHSC機能を制御できる可能性を示しており、さらには白血病などの造血器腫瘍の発症機構解明にもつながるものとして期待される。

Research Products

• [Journal Article] Molecular Pathogenesis and Treatment of Myelodysplastic Syndromes (2021)
  • Author(s): Nakajima Hideaki
  • Journal Title: Internal Medicine Volume: 60 Issue: 1 Pages: 15-23
  • DOI: 10.2169/internalmedicine.4214-19
  • NAID: 130007965379
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-01-01
  • Peer Reviewed
• [Journal Article] Predictive values of early suppression of tumorigenicity 2 for acute GVHD and transplant-related complications after allogeneic stem cell transplantation: prospective observational study. (2020)
  • Author(s): Matsumura A, Miyazaki T, Tachibana T, Ando T, Koyama M, Koyama S, Ishii Y, Takahashi H, Nakajima Y, Numata A, Yamamoto W, Motohashi K, Hagihara M, Matsumoto K, Fujisawa S, Nakajima H
  • Journal Title: Turk J Haematol. Volume: 37 Pages: 20-29
• [Journal Article] Impact of graft sources on immune reconstitution and survival outcomes following allogeneic stem cell transplantation. (2020)
  • Author(s): Ando T, Tachibana T, Tanaka M, Suzuki T, Ishiyama Y, Koyama S, Ogusa E, Numata A, Matsumoto K, Kanamori H, Nakajima H
  • Journal Title: Blood Adv. Volume: 4 Pages: 408-419
  • Peer Reviewed
• [Journal Article] Impact of Cytomegalovirus Reactivation and Natural Killer Reconstitution on Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation: A Single Center Analysis. (2020)
  • Author(s): Ando T, Suzuki T, Ishiyama Y, Koyama S, Tachibana T, Tanaka M, Kanamori H, Nakajima H
  • Journal Title: Biol Blood Marrow Transplant. Volume: 26 Pages: 171-177
  • Peer Reviewed
• [Journal Article] Yokohama Cooperative Study Group for Hematology (YACHT).: Impact of treatment-related weight changes from diagnosis to hematopoietic stem-cell transplantation on clinical outcome of acute myeloid leukemia. (2019)
  • Author(s): Ando T, Fujisawa S, Teshigawara H, Ogusa E, Ishii Y, Miyashita K, Motohashi K, Miyazaki T, Tachibana T, Hagihara M, Matsumoto K, Tanaka M, Hashimoto C, Koharazawa H, Fujimaki K, Taguchi J, Fujita H, Kanamori H, Yamazaki E, Nakajima H
  • Journal Title: Int J Hematol. Volume: 109 Pages: 673-683
• [Journal Article] Salvage and bridging to allogeneic hematopoietic cell transplantation with ponatinib in patients with relapsed or refractory Philadelphia chromosome-positive leukemia (2018)
  • Author(s): Tachibana Takayoshi、Koyama Satoshi、Andou Taiki、Ishiyama Yasufumi、Tanaka Masatsugu、Nakajima Hideaki、Kanamori Heiwa
  • Journal Title: International Journal of Hematology Volume: 109 Issue: 2 Pages: 162-168
  • DOI: 10.1007/s12185-018-02571-0
  • Peer Reviewed
• [Journal Article] Primary uterine lymphoma: The Yokohama Cooperative Study Group for Hematology (YACHT) study (2018)
  • Author(s): Ishii Yoshimi、Fujisawa Shin、Ando Taiki、Suzuki Taisei、Ishiyama Yasufumi、Kishimoto Kumiko、Hattori Yukako、Nakajima Yuki、Miyazaki Takuya、Takasaki Hirotaka、Matsumoto Kenji、Koharazawa Hideyuki、Taguchi Jun、Fujimaki Katsumichi、Sakai Rika、Nakajima Hideaki
  • Journal Title: Asia-Pacific Journal of Clinical Oncology Volume: 14 Issue: 5
  • DOI: 10.1111/ajco.13049
  • Peer Reviewed
• [Journal Article] Clinical Significance of Serum Ferritin at Diagnosis in Patients With Acute Myeloid Leukemia: A YACHT Multicenter Retrospective Study (2018)
  • Author(s): Tachibana Takayoshi、Andou Taiki、Tanaka Masatsugu、et al.
  • Journal Title: Clinical Lymphoma Myeloma and Leukemia Volume: 18 Issue: 6 Pages: 415-421
  • DOI: 10.1016/j.clml.2018.03.009
  • Peer Reviewed
• [Journal Article] Peripheral Blood Monocyte Count is a Predictor of Successful Peripheral Blood Stem Cell Harvest After Chemo-Mobilization in Patients with Malignant Lymphoma (2018)
  • Author(s): Ishii Yoshimi、Fujisawa Shin、Nigauri Chika、Ando Taiki、Suzuki Taisei、Ogusa Eriko、Miyashita Kazuho、Motohashi Kenji、Nakajima Hideaki
  • Journal Title: Indian Journal of Hematology and Blood Transfusion Volume: 34 Issue: 2 Pages: 347-349
  • DOI: 10.1007/s12288-017-0848-2
  • Peer Reviewed
• [Journal Article] Anemia associated with worse outcome in diffuse large B-cell lymphoma patients: a single-center retrospective study (2018)
  • Author(s): Matsumoto Kenji、Fujisawa Shin、Ando Taiki、Koyama Megumi、Koyama Satoshi、Ishii Yoshimi、Numata Ayumi、Yamamoto Wataru、Motohashi Kenji、Hagihara Maki、Nakajima Hideaki
  • Journal Title: Turkish Journal of Hematology Volume: 35 Pages: 181-184
  • DOI: 10.4274/tjh.2017.0437
  • Peer Reviewed
• [Journal Article] Septicemia from Lactobacillus rhamnosus GG, from a Probiotic Enriched Yogurt, in a Patient with Autologous Stem Cell Transplantation (2018)
  • Author(s): Koyama Satoshi、On behalf of the Yokohama Cooperative Study Group for Hematology (YACHT)、Fujita Hiroyuki、Shimosato Takeshi、Kamijo Aki、Ishiyama Yasufumi、Yamamoto Eri、Ishii Yoshimi、Hattori Yukako、Hagihara Maki、Yamazaki Etsuko、Tomita Naoto、Nakajima Hideaki
  • Journal Title: Probiotics and Antimicrobial Proteins Volume: Feb 17 Issue: 1 Pages: 295-298
  • DOI: 10.1007/s12602-018-9399-6
  • Peer Reviewed
• [Journal Article] 10-year complete remission in a Philadelphia chromosome-positive acute lymphoblastic leukemia patient using imatinib without high-intensity chemotherapy or allogeneic stem cell transplantation (2018)
  • Author(s): Fujimaki Katsumichi、Hattori Yukako、Nakajima Hideaki
  • Journal Title: International Journal of Hematology Volume: 107 Issue: 6 Pages: 709-711
  • DOI: 10.1007/s12185-017-2382-2
  • Peer Reviewed
• [Journal Article] Serum ferritin level is a prognostic marker in patients with peripheral T-cell lymphoma. (2017)
  • Author(s): Satoshi Koyama, Shin Fujisawa, Reina Watanabe, Megumi Itabashi, Daisuke Ishibashi, Yoshimi Ishii, Yukako Hattori, Yuki Nakajima, Kenji Motohashi, Hirotaka Takasaki, Rika Kawasaki, Chizuko Hashimoto, Etsuko Yamazaki, Hideyuki Koharazawa, Sachiya Takemura, Naoto Tomita, Rika Sakai, Shigeki Motomura, Hideaki Nakajima
  • Journal Title: International Journal of Laboratory Hematology Volume: 39 Issue: 1 Pages: 112-112
  • DOI: 10.1111/ijlh.12592
  • Peer Reviewed
• [Journal Article] CXorf48 is a potential therapeutic target for achieving treatment-free remission in CML patients (2017)
  • Author(s): Matsushita M, Ozawa K, Suzuki T, Nakamura M, Nakano N, Kanchi S, Ichikawa D, Matsuki E, Sakurai M, Karigane D, Kasahara H, Tsukamoto N, Shimizu T, Mori T, Nakajima H, Okamoto S, Kawakami Y, Hattori Y
  • Journal Title: Blood Cancer J. Volume: 7 Issue: 9 Pages: 601-601
  • DOI: 10.1038/bcj.2017.84
  • Peer Reviewed / Open Access
• [Journal Article] The Standard International Prognostic Index for Predicting the Risk of CNS Involvement in DLBCL without Specific Prophylaxis. (2017)
  • Author(s): Tomita N, Yokoyama M, Yamamoto W, Watanabe R, Shimazu Y, Masaki Y, Tsunoda S, Hashimoto C, Murayama K, Yano T, Okamoto R, Kikuchi A, Tamura K, Sato K, Sunami K, Shibayama H, Takimoto R, Ohshima R, Takahashi H, Moriuchi Y, Kinoshita T, Yamamoto M, Numata A, Nakajima H, Miura I, Takeuchi K.
  • Journal Title: Leuk Lymphoma Volume: 59 Issue: 1 Pages: 1-8
  • DOI: 10.1080/10428194.2017.1330541
  • Peer Reviewed / Open Access
• [Journal Article] Epigenetic dysregulation of hematopoietic stem cells and preleukemic state. (2017)
  • Author(s): Kunimoto H, Nakajima H.
  • Journal Title: Int J Hematol. Volume: 106 Issue: 1 Pages: 34-44
  • DOI: 10.1007/s12185-017-2257-6
  • Peer Reviewed
• [Journal Article] Guest editorial: Hematopoietic stem cells. (2017)
  • Author(s): Nakajima H
  • Journal Title: Int J Hematol. Volume: 106 Issue: 1 Pages: 16-17
  • DOI: 10.1007/s12185-017-2267-4
  • Peer Reviewed
• [Presentation] Successful treatment of systemic Erdheim-Chester disease with interferon-alpha. (2019)
  • Author(s): Mao Wakamatsu, Takuya Miyazaki, Ayako Matsumura, Haruka Teshigawara, Hiroshi Teranaka, Satoshi Koyama, Hiroyuki Takahashi, Hiroyoshi Kunimoto, Makiko Enaka, Daisuke Kamimura, Maki Hagihara, Kenji Matsumoto, Etsuko Yamazaki, Hideaki Nakajima
  • Organizer: 第81回日本血液学会学術集会, 東京
• [Presentation] Risk factors of allogeneic hematopoietic stem cell transplantation for myelodysplastic syndromes. (2019)
  • Author(s): Haruka Teshigawara，Maki Hagihara，Hiroshi Teranaka, Jun Aoki，Satoshi Koyama，Hiroyuki Takahashi, Yuki Nakajima, Hiroyoshi Kunimoto, Takayoshi Tachibana，Takuya Miyazaki, Kenji Matsumoto，Masatsugu Tanaka，Etsuko Yamazaki，Jun Taguchi, Shin Fujisawa, Heiwa Kanamori, Hideaki Nakajima
  • Organizer: 第81回日本血液学会学術集会, 東京
• [Presentation] Clinical impact of cigarette smoking on outcomes after allo-HSCT. (2019)
  • Author(s): Takuma Ohashi，Jun Aoki，Taiki Ando，Yasufumi Ishiyama, Yoshimi Ishii，Kazuho Miyashita，Yuki Nakajima，Takayoshi Tachibana， Maki Hagihara，Kenji Matsumoto，Masatsugu Tanaka, Heiwa Kanamori，Shin Fujisawa，Hideaki Nakajima
  • Organizer: 第81回日本血液学会学術集会, 東京
• [Presentation] Risk stratification in patients with essential thrombocythemia: single center study. (2019)
  • Author(s): Yoshimi Ishii，Shin Fujisawa，Marika Hatakeyama，Mayumi Tokunaga， Takuma Ohashi，Jun Aoki，Kazuho Miyashita，Yuki Nakajima, Hideaki Nakajima
  • Organizer: 第81回日本血液学会学術集会, 東京
• [Presentation] Metabolic regulation of hematopoietic stem cells by O-linked N-acetylglucosamine transferase (2018)
  • Author(s): 村上 紘一、黒滝 大翼、川瀬 航、相馬 俊介、福地 由美、國本 博義、吉見 竜介、小出 周平、大島 基彦、小田 真由美、洪 実、菱木 貴子、早川 典代、松浦 友美、柳澤 輝一、小林 央、原口 美帆、岩間 厚志、岡本 真一郎、田久保 圭誉、田村 智彦、中島 秀明
  • Organizer: 幹細胞シンポジウム
• [Presentation] Metabolic Regulation Of Hematopoietic Stem Cells By O-linked N-acetylglucosamine Transferase (2018)
  • Author(s): Koichi Murakami, Daisuke Kurotaki, Wataru Kawase, et al.
  • Organizer: JSH国際シンポジウム
• [Presentation] Metabolic regulation of hematopoietic stem cells by O-linked N-acetylglucosamine transferase (2018)
  • Author(s): Koichi Murakami, Daisuke Kurotaki, Wataru Kawase, et al.
  • Organizer: 47th International Society for Experimental Hematology Annual Meeting
• [Presentation] O-GlcNAcylation is critical for mitochondrial dynamics in hematopoietic stem cells (2018)
  • Author(s): Koichi Murakami, Daisuke Kurotaki, Wataru Kawase, et al.
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Regulation of mitophagy by O-linked N-acetylglucosamine transferase is essential for hematopoietic stem cell maintenance (2018)
  • Author(s): Koichi Murakami, Daisuke Kurotaki, Wataru Kawase, et al.
  • Organizer: 60th American Society of Hematology Annual Meeting