Understanding the immune pathophysiology in bone marrow failure patients with HLA-B*54:01

• Project/Area Number: 19K17823
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kanazawa University
• Principal Investigator: Hosokawa Kohei 金沢大学, 附属病院, 助教 (10786239)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 再生不良性貧血 / HLA / iPS細胞 / 造血不全 / 免疫学

Outline of Research at the Start

再生不良性貧血（再不貧）は、造血幹前駆細胞に対する細胞傷害性T細胞の攻撃がきっかけとなって発症する自己免疫疾患である。これまでの研究により、再不貧では特定のHLAクラスIアリルを欠失した造血幹前駆細胞が細胞傷害性T細胞からの攻撃を免れた結果、造血を支持することが分かっている。再不貧の白血球で欠失しやすいHLAクラスIの中でも、HLA-B5401を欠失した血球を持つ再不貧患者はほとんどが男性であることが最近の研究により明らかになった。本研究では、男性に偏って発症するHLA-B5401欠失血球陽性の再不貧の免疫病態と、HLA-B5401が提示する再不貧の自己抗原を明らかにする。

Outline of Final Research Achievements

The purpose of the study is to understand pathophysiology in aplastic anemia (AA) patients with HLA-B*54:01 lacking cells and autoantigens presented by HLA-B5401. We identified T-cell receptor sequence in AA patients with HLA-B5401 lacking cells. We also identified a common nonsense mutation in exon 1 of different HLA-A and -B alleles in HLA-lacking granulocytes from AA patients. A droplet digital PCR (ddPCR) assay revealed that HLA-B*54:01 mutation was the second most frequent HLA-B allele in AA patients.

Academic Significance and Societal Importance of the Research Achievements

HLA-B*54:01を保有する再不貧例において、6pLOHを有する症例の頻度が高かったことや、HLA-B*54:01に体細胞変異を有する症例が認められたことから、HLA-B5401は造血幹細胞におけるT細胞への自己抗原提示に重要な役割をしている可能性が示唆された。HLA-B5401欠失血球を認める症例は高率に男性であり、アンドロゲン受容体（AR）のCAG リピート数が短縮していた。このため、ARがHLA-B5401欠失血球陽性例の再不貧発症に関与しており、男性に偏って発症する理由となっている可能性が考えられた。

Research Products

• [Journal Article] High-dose romiplostim accelerates hematologic recovery in patients with aplastic anemia refractory to eltrombopag (2021)
  • Author(s): Hosokawa Kohei, Yamazaki Hirohito, Tanabe Mikoto, Imi Tatsuya, Sugimori Naomi, Nakao Shinji
  • Journal Title: Leukemia Volume: 35 Issue: 3 Pages: 906-909
  • DOI: 10.1038/s41375-020-0950-6
  • Peer Reviewed
• [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] Hematopoietic stem progenitor cells lacking HLA differ from those lacking GPI-anchored proteins in the hierarchical stage and sensitivity to immune attack in patients with acquired aplastic anemia (2021)
  • Author(s): Yoroidaka T, Hosokawa K, Imi T, Mizumaki H, Katagiri T, Ishiyama K, Yamazaki H, Azuma F, Nanya Y, Ogawa S, Nakao S
  • Journal Title: Leukemia Volume: in press Issue: 11 Pages: 3257-3267
  • DOI: 10.1038/s41375-021-01202-8
  • 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
• [Journal Article] Acquired aplastic anemia (2019)
  • Author(s): Hosokawa K, Nakao S
  • Journal Title: Rinsho Ketsueki Volume: 60 Issue: 5 Pages: 417-422
  • DOI: 10.11406/rinketsu.60.417
  • NAID: 130007659585
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Clonal hematopoiesis by SLIT1-mutated hematopoietic stem cells due to a breakdown of the autocrine loop involving Slit1 in acquired aplastic anemia (2019)
  • Author(s): Hosokawa K, Mizumaki H, Elbadry M, Saito C, Espinoza JL, An DTT, Katagiri T, Harashima A, Kikuchi A, Kanai A, Matsui H, Inaba T, Taniwaki M, Yamamoto Y, Nakao S
  • Journal Title: Leukemia Volume: 33 Issue: 11 Pages: 2732-2766
  • DOI: 10.1038/s41375-019-0510-0
  • Peer Reviewed / Int'l Joint Research
• [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, Hiroki Mizumaki, Takeshi Yoroidaka, Hiroyuki Maruyama, Tatsuya Imi, Noriaki Tsuji, Ryota Urushihara, Mikoto Tanabe, Yoshitaka Zaimoku, Mai Anh Nguyen, Dung Tran, Ken Ishiyama, Hirohito Yamazaki, Takamasa Katagiri, Kazuyoshi Hosomichi, Atsushi Tajima, Fumihiro Azuma, Seishi Ogawa, Shinji Nakao
  • Organizer: 2020 ASH annual meeting
  • Int'l Joint Research
• [Presentation] High-dose romiplostim accelerates hematologic recovery in patients with aplastic anemia refractory to eltrombopag. (2020)
  • Author(s): Kohei Hosokawa, Hirohito Yamazaki, Mikoto Tanabe, Tatsuya Imi, Keiji Aoshima, Naomi Sugimori, Shinji Nakao
  • Organizer: 25th Congress of European Hematology Association.
  • Int'l Joint Research
• [Presentation] Epigenetic Loss of the HLA-DR15 Expression on Hematopoietic Stem Progenitor Cells in Patients with Acquired Aplastic Anemia Characterized By Cyclosporine Dependency: A Novel Mechanism Underlying the Immune Escape of Hematopoietic Stem Progenitor Cells (2020)
  • Author(s): Noriaki Tsuji, Kohei Hosokawa, Ryota Urushihara, Mikoto Tanabe, Hiroyuki Takamatsu, Ken Ishiyama, Hirohito Yamazaki, Shinji Nakao
  • Organizer: 2020 ASH annual meeting
  • Int'l Joint Research
• [Presentation] Identification of T-Cell Receptors Specific to Antigens Presented By HLA-B4002 and B5401 in Acquired Aplastic Anemia (2019)
  • 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: 2019 ASH annual meeting
  • Int'l Joint Research
• [Presentation] A Common HLA Allelic Mutation of exon1 in Leukocytes Defines Class I Alleles Responsible for Autoantigen Presentation of Acquired Aplastic Anemia (2019)
  • Author(s): Hiroki Mizumaki, Kazuyoshi Hosomichi, Tatsuya Imi, Noriaki Tsuji, Tanabe Mikoto, Dung Cao Tran, Mai Anh Thi Nguyen, Yoshitaka Zaimoku, Kohei Hosokawa, Takamasa Katagiri, Fumihiro Azuma, Atsushi Tajima, Shinji Nakao
  • Organizer: 2019 ASH annual meeting
  • Int'l Joint Research
• [Presentation] Distinct Escape Mechanisms of HLA Class I Allele-Lacking Hematopoietic Stem Progenitor Cells (HSPCs) from GPI-Deficient HSPCs in Acquired Aplastic Anemia (2019)
  • Author(s): Noriaki Tsuji, Kohei Hosokawa, Takeshi Yoroidaka, Tanabe Mikoto, Hiroki Mizumaki, Shinji Nakao
  • Organizer: 2019 ASH annual meeting
  • Int'l Joint Research
• [Presentation] A GPI-Anchored Protein, CD109, Protects Hematopoietic Progenitor Cells from Erythroid Differentiation Induced By TGF-β (2019)
  • Author(s): Tanabe Mikoto, Mai Anh Thi Nguyen, Kohei Hosokawa, Noriharu Nakagawa, Luis Espinoza, Hirohito Yamazaki, Shinji Nakao
  • Organizer: 2019 ASH annual meeting
  • Int'l Joint Research
• [Presentation] Olfactomedin 4 Inhibits Erythroid Differentiation of Leukemic Cell Lines Induced By TGF-β: A Model of Preferential Commitment of Del(13q) Hematopoietic Stem Cells in Immune-Mediated Bone Marrow Failure (2019)
  • Author(s): Mai Anh Thi Nguyen, Kohei Hosokawa, Tanabe Mikoto, Md Mohiuddin, Takeshi Yoroidaka, Hiroki Mizumaki, Tatsuya Imi, Masaya Ueno, Atsushi Hirao, Shinji Nakao
  • Organizer: 2019 ASH annual meeting
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] ＨＬＡクラスＩアレル欠失血球の検出方法 (2020)
  • Inventor(s): 水牧裕希, 中尾眞二, 細川 晃平
  • Industrial Property Rights Holder: 水牧裕希, 中尾眞二, 細川 晃平
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020
  • Overseas
• [Patent(Industrial Property Rights)] HLAクラスIアレルにおける機能喪失型共通変異の検出方法 (2019)
  • Inventor(s): 水牧裕希、中尾眞二、細川晃平
  • Industrial Property Rights Holder: 水牧裕希、中尾眞二、細川晃平
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-090219
  • Filing Date: 2019