The role of CD109 and TGF-beta for the preferential commitment of PIGA mutant HSPCs in immune-mediated bone marrow failure.

• Project/Area Number: 15K09496
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kanazawa University
• Principal Investigator: Yamazaki Hirohito 金沢大学, 附属病院, 准教授 (50361994)
• Co-Investigator(Renkei-kenkyūsha): NAKAO Shinji 金沢大学, 医学系, 教授 (70217660)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 再生不良性貧血 / CD109 / TGF‐β / PIGA遺伝子変異造血幹前駆細胞 / PIGA遺伝子変異 / GPIアンカー膜蛋白 / PNH型血球 / TGF-β / 造血抑制因子

Outline of Final Research Achievements

To determine whether a TGF-beta (b) co-receptor CD109 on hematopoietic stem progenitor cells (HSPCs) play a role in the preferential commitment of PIGA mutant HSPCs in patients with immune-mediated bone marrow failure (BMF), we established CD109-knock out (KO) TF-1, a GM-CSF-dependent myeloid leukemia cell line, using the CRIPR/Cas9 system, and compared the sensitivity of CD109KO TF-1 cells to TGF-b to that of wild-type (WT) TF-1 cells. The TGF-b treatment induced pSMAD2 in CD109KO TF-1 cells to a significantly lesser degree than in WT TF-1 cells. The proliferation of CD109KO TF-1 was inhibited by TGF-b also to a lesser degree than WT TF-1 cells. The results suggest that CD109, a glycosylphosphatidylinositol anchor protein, plays an enhancing role in the TGF-b signaling in HSPCs, and the lack of CD109 may make the HSPCs less sensitive to TGF-b, leading to the preferential commitment of the PIGA mutant HSPCs in immune-mediated BMF, in which TGF-b suppresses activation of WT HSPCs.

Research Products

• [Journal Article] Outcome of Second Transplantation Using Umbilical Cord Blood for Graft Failure after Allogeneic Hematopoietic Stem Cell Transplantation for Aplastic Anemia. (2017)
  • Author(s): Onishi Y, Mori T, Kako S, Koh H, Uchida N, Kondo T, Kobayashi T, Yabe H, Miyamoto T, Kato K, Suzuki R, Nakao S, Yamazaki H
  • Journal Title: Biol Blood Marrow Transplant Volume: 23 Issue: 12 Pages: 2137-2142
  • DOI: 10.1016/j.bbmt.2017.08.020
  • Peer Reviewed
• [Journal Article] Cyclosporine restores hematopoietic function by compensating for decreased Tregs in patients with pure red cell aplasia and acquired aplastic anemia. (2016)
  • Author(s): Dao AT, Yamazaki H, Takamatsu H, Sugimori C, Katagiri T, Maruyama H, Zaimoku Y, Maruyama K, Ly TQ, Espinoza L, Nakao S
  • Journal Title: Ann Hematol Volume: 95 Issue: 5 Pages: 771-781
  • DOI: 10.1007/s00277-016-2629-7
  • Peer Reviewed
• [Journal Article] Clinical significance and origin of leukocytes that lack HLA-A allele expression in patients with acquired aplastic anemia (2016)
  • Author(s): Maruyama H, Katagiri T, Kashiwase K, Shiina T, Sato-Otsubo A, Zaimoku Y, Maruyama K, Hosokawa K, Ishiyama K, Yamazaki H, Inoko H, Ogawa S, Nakao S
  • Journal Title: Exp Hematol. Volume: 44 Issue: 10 Pages: 931-939
  • DOI: 10.1016/j.exphem.2016.05.013
  • NAID: 120005895697
  • Peer Reviewed / Open Access
• [Journal Article] Hypomegakaryocytic thrombocytopenia (HMT): an immune-mediated bone marrow failure characterized by an increased number of PNH-phenotype cells and high plasma thrombopoietin levels. (2016)
  • Author(s): Saito C, Ishiyama K, Yamazaki H, Zaimoku Y, Nakao S.
  • Journal Title: Br J Haematol Volume: 175 Issue: 2 Pages: 246-251
  • DOI: 10.1111/bjh.14210
  • Peer Reviewed
• [Journal Article] Acquired aplastic anemia (2016)
  • Author(s): 山崎 宏人
  • Journal Title: Rinsho Ketsueki Volume: 57 Issue: 2 Pages: 91-97
  • DOI: 10.11406/rinketsu.57.91
  • NAID: 130005132705
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Hematopoietic stem cell transplantation for acquired aplastic anemia (2015)
  • Author(s): 山崎 宏人
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 10 Pages: 2153-2159
  • DOI: 10.11406/rinketsu.56.2153
  • NAID: 130005103281
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Increased glycosylphosphatidylinositol-anchored protein-deficient granulocytes define a benign subset of bone marrow failures in patients with trisomy 8. (2014)
  • Author(s): Hosokawa K, Sugimori N, Katagiri T, Sasaki Y, Saito C, Seiki Y, Mochizuki K, Yamazaki H, Takami A, Nakao S.
  • Journal Title: Eur J Haemat Volume: 18 Issue: 3 Pages: 230-238
  • DOI: 10.1111/ejh.12484
  • NAID: 120005661927
  • Peer Reviewed / Open Access
• [Presentation] 再生不良性貧血の病態診断と治療選択 (2017)
  • Author(s): 山崎宏人
  • Organizer: 第65回日本輸血・細胞治療学会総会
• [Presentation] Relatively low sensitivity of CD109(-) hematopoietic stem/progenitor cells (HSPCs) to TGF-β: A possible mechanism responsible for the preferential commitment of PIGA mutant HSPCs in immune-mediated bone marrow failure. (2016)
  • Author(s): Nakagawa N, Hosokawa K, Espinosa L, Maruyama K, Katagiri K, Yamazaki H, Nakao S
  • Organizer: 第58回米国血液学会議
  • Place of Presentation: サンディエゴ（アメリカ）
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Prevalence pf PNH-type cells in cases of chronic thrombocytopenia that can be diagnosed with ITP. (2016)
  • Author(s): Yamazaki H, Sugimori N, Maruyama K, Zaimoku Y, Maruyama H, Nakagawa N, Saito C, Imi T, Sugimori C, Ishiyama K, Nakao S
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-13
• [Presentation] Evidence That T Cells Specific for Non-Hematopoietic Cells Trigger the Development of Acquired Aplastic Anemia (2015)
  • Author(s): Tatsuya Imi, Hiroyuki Maruyama, Takamasa Katagiri, Yoshitaka Zaimoku, Kana Maruyama, Noriharu Nakagawa, Kohei Hosokawa, Ken Ishiyama, Hirohito Yamazaki, Koichi Kashiwase, Shinji Nakao
  • Organizer: 57th ASH Annual Meeting
  • Place of Presentation: オーランド（アメリカ）
  • Year and Date: 2015-12-05
• [Presentation] Evidence for a Common Immune Pathophysiology in Acquired Aplastic Anemia and Ulcerative Colitis (2015)
  • Author(s): Noriharu Nakagawa, Hiroyuki Maruyama, Yoshitaka Zaimoku, Kana Maruyama, Chizuru Saito, Takamasa Katagiri, Kohei Hosokawa, Ken Ishiyama, Hirohito Yamazaki, Shinji Nakao
  • Organizer: 57th ASH Annual Meeting
  • Place of Presentation: オーランド（アメリカ）
  • Year and Date: 2015-12-05
• [Presentation] 再生不良性貧血に対する造血幹細胞移植 (2015)
  • Author(s): 山崎 宏人
  • Organizer: 第77回日本血液学会学術集会（教育講演）
  • Place of Presentation: ホテル金沢（石川県金沢市）
  • Year and Date: 2015-10-16
• [Presentation] HLA-A allele-lacking leukocytes as a therapeutic response marker in patients with aplastic anemia (2015)
  • Author(s): 丸山 裕之、片桐 孝和、材木 義隆、丸山 佳奈、山﨑 宏人、中尾 眞二
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 石川県立音楽堂（石川県金沢市）
  • Year and Date: 2015-10-16
• [Presentation] Whole blood transcriptional profiling for diagnosing autoimmune hematopoietic failure (2015)
  • Author(s): 材木 義隆、中川 紀温、井美 達也、丸山 佳奈、丸山 裕之、片桐 孝和、高松 博幸、石山 謙、山﨑 宏人、中尾 眞二
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: ホテル日航金沢（石川県金沢市）
  • Year and Date: 2015-10-16