Elucidation of the fundamental mechanism underlying hematopoietic control changes through a novel immune evasion mechanism in autoimmune bone marrow failure

• Project/Area Number: 20K08707
• 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: Kanazawa University
• Principal Investigator: Katagiri Takamasa 金沢大学, 保健学系, 准教授 (60621159)
• Co-Investigator(Kenkyū-buntansha): 細川 晃平 金沢大学, 附属病院, 助教 (10786239)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); 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); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: iPS細胞 / HLA / 自己免疫疾患 / 造血幹細胞 / 骨髄移植 / 免疫不全マウス / 免疫学

Outline of Research at the Start

自己免疫性骨髄不全は、造血幹細胞に対する自己の細胞傷害性T細胞の攻撃が発端となって発症する造血不全である。本研究では、自己免疫性骨髄不全において、造血幹細胞が異常免疫から回避する新たな手段を同定することを目的とし、変異遺伝子の挙動を未治療時から治療後寛解に至る過程で経時的に解析し、変異遺伝子による時間的な造血制御の変遷を明らかにする。また、患者のiPS細胞由来造血幹細胞を免疫不全マウスへ移植することにより確立した「特定の表現型を有するヒト造血マウスモデル」を用いて、恒常的な造血を目的とした造血幹細胞の「免疫回避手段の多様性」および、それに伴う「造血制御の変容」を解明する。

Outline of Final Research Achievements

Aplastic anemia is a disorder that results in hematopoietic failure due to T cells attacking hematopoietic progenitor cells (HSPCs). However, the mechanisms that regulate hematopoietic control and immune evasion in HSPCs are not yet fully understood. This study aimed to investigate the expression of CXCR4, a chemokine involved in hematopoietic control, in HSPCs with diverse phenotypes. The results suggest that diverse immune evasion mechanisms and changes in hematopoietic control are required for steady hematopoiesis among HSPCs. Transplantation experiments using HSPCs induced from patient iPS cells revealed that CXCR4 expression may be controlled as epigenetic memory, which explains the observed changes in hematopoietic control in autoimmune aplastic anemia. These findings provide insights into hematopoietic control and CXCR4 expression in HSPCs, as well as potential novel therapies for hematopoietic failure.

Academic Significance and Societal Importance of the Research Achievements

自己免疫性骨髄不全は、造血幹前駆細胞に対する自己の細胞傷害性T細胞の攻撃が発端となり発症する造血不全である。本研究において、患者iPS細胞から誘導した造血幹前駆細胞を用いた実験により、造血制御関連ケモカインであるCXCR4の発現が多様な表現型を有する造血幹前駆細胞の間で乖離しているとともに、その発現がepigenetic memoryとして制御されている可能性を示した。本研究成果は、造血制御機構の解明に大きく貢献するとともに、骨髄不全患者の良性および前がん性クローン性造血の鑑別に役立つ可能性が考えられる。また、将来的には個別化医療の進展にも繋がることが期待される。

Research Products

• [Journal Article] Hematopoietic stem progenitor cells with malignancy‐related gene mutations in patients with acquired aplastic anemia are characterized by the increased expression of CXCR4 (2022)
  • Author(s): Katagiri Takamasa,Espinoza Luis,Uemori Mizuho,Ikeda Honoka,Hosokawa Kohei,Ishiyama Ken,Yoroidaka Takeshi,Imi Tatsuya,Takamatsu Hiroyuki,Ozawa Tatsuhiko,Kishi Hiroyuki,Yamamoto Yasuhiko,Elbadry Mahmoud,Yoshida Yoshinori,Chonabayashi Kazuhisa,Takenaka Katsuto,Akashi Koichi,Nannya Yasuhito,Ogawa Seishi,Nakao Shinji
  • Journal Title: eJHaem Volume: 3 Issue: 3 Pages: 669-680
  • DOI: 10.1002/jha2.515
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Frequent HLA-DR loss on hematopoietic stem progenitor cells in patients with cyclosporine-dependent aplastic anemia carrying HLA-DR15 (2022)
  • Author(s): Tsuji Noriaki、Hosokawa Kohei、Urushihara Ryota、Tanabe Mikoto、Katagiri Takamasa、Ozawa Tatsuhiko、Takamatsu Hiroyuki、Ishiyama Ken、Yamazaki Hirohito、Kishi Hiroyuki、Ogawa Seishi、Nakao Shinji
  • Journal Title: Leukemia Volume: 36 Issue: 6 Pages: 1666-1675
  • DOI: 10.1038/s41375-022-01549-6
  • Peer Reviewed
• [Journal Article] The GPI-anchored protein CD109 protects hematopoietic progenitor cells from undergoing erythroid differentiation induced by TGF-β (2021)
  • Author(s): Tanabe Mikoto、Hosokawa Kohei、Nguyen Mai Anh Thi、Nakagawa Noriharu、Maruyama Kana、Tsuji Noriaki、Urushihara Ryota、Espinoza Luis、Elbadry Mahmoud I.、Mohiuddin Md、Katagiri Takamasa、Ono Masanori、Fujiwara Hiroshi、Chonabayashi Kazuhisa、Yoshida Yoshinori、Yamazaki Hirohito、Hirao Atsushi、Nakao Shinji
  • Journal Title: Leukemia Volume: 36 Issue: 3 Pages: 847-855
  • DOI: 10.1038/s41375-021-01463-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] HLA class I allele-lacking leukocytes predict rare clonal evolution to MDS/AML in patients with acquired aplastic anemia. (2021)
  • Author(s): Hosokawa K, Mizumaki H, Yoroidaka T, Maruyama H, Imi T, Tsuji N, Urushihara R, Tanabe M, Zaimoku Y, Nguyen MAT, Tran DC, Ishiyama K, Yamazaki H, Katagiri T, Takamatsu H, Hosomichi K, Tajima A, Azuma F, Ogawa S, Nakao S.
  • Journal Title: Blood Volume: － Issue: 25 Pages: 3576-3580
  • DOI: 10.1182/blood.2020010586
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Resistance of KIR Ligand-Missing Leukocytes to NK Cells In Vivo in Patients with Acquired Aplastic Anemia. (2020)
  • Author(s): Nguyen MAT, Hosokawa K, Yoroidaka T, Maruyama H, Espinoza JL, Elbadry MI, Mohiuddin M, Tanabe M, Katagiri T, Nakagawa N, Chonabayashi K, Yoshida Y, Arima N, Kashiwase K, Saji H, Ogawa S, Nakao S.
  • Journal Title: Immunohorizons Volume: 4 Issue: 7 Pages: 430-441
  • DOI: 10.4049/immunohorizons.2000046
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A frequent nonsense mutation in exon 1 across certain HLA-A and -B alleles in leukocytes of patients with acquired aplastic anemia. (2020)
  • Author(s): Mizumaki H, Hosomichi K, Hosokawa K, Yoroidaka T, Imi T, Zaimoku Y, Katagiri T, Nguyen MAT, Tran DC, Elbadry MIY, Chonabayashi K, Yoshida Y, Takamatsu H, Ozawa T, Azuma F, Kishi H, Fujii Y, Ogawa S, Tajima A, Nakao S.
  • Journal Title: Haematologica Volume: － Issue: 6 Pages: 247809-247809
  • DOI: 10.3324/haematol.2020.247809
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] HLA Class I Allele-Specific Pathology Defines Clinical Manifestations of Immune Aplastic Anemia. (2022)
  • Author(s): Yoshitaka Zaimoku, Hiroki Mizumaki, Takeshi Yoroidaka, Noriharu Nakagawa, Tatsuya Imi, Hiroyuki Maruyama, Mikoto Tanabe, Noriaki Tsuji, Ryota Urushihara, Kohei Hosokawa, Takamasa Katagiri, Hiroyuki Takamatsu, Ken Ishiyama, Hirohito Yamazaki, Toshihiro Miyamoto, Shinji Nakao.
  • Organizer: 64th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] HSPCs with MDS-related mutations in aplastic anemia are characterized by increased CXCR4 expression. (2022)
  • Author(s): 片桐孝和、Juis Espinoza、上森瑞穂、池田ほのか、細川晃平、石山謙、鎧高健志、井美達也、高松博幸、小澤龍彦、岸裕幸、山本靖彦、Mahmoud Elbadry、吉田善紀、蝶名林和久、竹中克斗、赤司浩一、南谷泰仁、小川誠司、中尾眞二.
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] HLA class I allele-lacking leukocytes prevent the development of secondary PNH in aplastic anemia. (2022)
  • Author(s): 細川晃平、水牧裕希、鎧高健志 、丸山裕之 、井美達也 、辻紀章、漆原涼太、 田辺命 、材木義隆、Maianh Thinguyen、Dung Cao Tran Thi、石山謙 、山崎宏人 、片桐孝和 、高松博幸 、細道一善 、田嶋敦 、東史啓 、小川誠司 、宮本敏浩 、中尾眞二.
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] SCFおよびTNF-βによる限局的造血制御. (2022)
  • Author(s): 長原里紗、内沢萌々、岩﨑寛香、上森瑞穂、片桐孝和.
  • Organizer: 第46回北陸臨床病理集談会
• [Presentation] IFN-γによる広汎性造血制御. (2022)
  • Author(s): 岩﨑寛香、内沢萌々、長原里紗、上森瑞穂、片桐孝和.
  • Organizer: 第46回北陸臨床病理集談会
• [Presentation] 再生不良性貧血における体細胞変異を有する造血幹前駆細胞の特性. (2022)
  • Author(s): 上森瑞穂、池田ほのか、岩﨑寛香、片桐孝和.
  • Organizer: 第46回北陸臨床病理集談会
• [Presentation] The Copy Number of Disease-Associated HLA Alleles Predicts the Response to Immunosuppressive Therapy in Acquired Aplastic Anemia (2021)
  • Author(s): Yoshitaka Zaimoku, Hiroki Mizumaki, Tatsuya Imi, Kohei Hosokawa, Hiroyuki Maruyama, Takamasa Katagiri, Takeshi Yoroidaka, Noriharu Nakagawa, Mikoto Tanabe, Noriaki Tsuji, Ryota Urushihara, Hiroyuki Takamatsu, Hirohito Yamazaki, Ken Ishiyama, Shinji Nakao
  • Organizer: 63th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Presentation] Frequencies and clinical significance of HLA alleles in acquired aplastic anemia (2021)
  • Author(s): Yoshitaka Zaimoku, Kohei Hosokawa, Takamasa Katagiri, Hiroyuki Maruyama, Tatsuya Imi, Hiroki Mizumaki, Takeshi Yoroidaka, Mikoto Tanabe, Ryota Urushihara, Noriaki Tsuji, Hiroyuki Takamatsu, Hirohito Yamazaki, Ken Ishiyama, Shinji Nakao
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Clonal Hematopoiesis By HLA Class I Allele-Lacking Hematopoietic Stem Cells and Concomitant Aberrant Stem Cells Is Rarely Associated with Clonal Evolution to Secondary Myelodysplastic Syndrome and Acute Myeloid Leukemia in Patients with Acquired Aplastic Anemia. (2020)
  • Author(s): Kohei Hosokawa, Eiji Kobayashi, Yoshiki Akatsuka, Luis Espinoza, Noriharu Nakagawa, Tanabe Mikoto, Noriaki Tsuji, Takeshi Yoroidaka, Hiroki Mizumaki, Thi Mai Anh Nguyen, Takamasa Katagiri, Kiyomi Shitaoka, Hiroshi Hamana, Hiroyuki Kishi, Shinji Nakao,
  • Organizer: 62th American Society of Hematology Annual Meeting
  • Int'l Joint Research
• [Remarks] 金沢大学研究者情報
  • URL: https://ridb.kanazawa-u.ac.jp/public/detail.php?id=4033.
• [Remarks] 金沢大学研究者情報
  • URL: http://ridb.kanazawa-u.ac.jp/public/detail.php?id=4033