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Identification of predictors of response to thrombopoietin receptor agonists in refractory aplastic anemia

Research Project

Project/Area Number 18K08318
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionKanazawa University

Principal Investigator

Yamazaki Hirohito  金沢大学, 附属病院, 准教授 (50361994)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords再生不良性貧血 / トロンボポエチン受容体作動薬 / HLAクラスⅠアリル欠失血球 / GPIアンカー型蛋白欠失血球 / エルトロンボパグ / ロミプロスチム / GPIアンカー膜蛋白欠失血球 / HLAクラスⅠアレル欠失血球 / 細胞表面抗原解析 / TPO受容体作動薬
Outline of Final Research Achievements

To gain insight into the origin of HLA class I allele-lacking (HLA[-]) and GPI-anchored membrane protein-deficient (GPI[-]) cells and mechanisms underlying escape of these marker(-) hematopoietic stem cells (HSCs) in patients with acquired aplastic anemia (AA), we analyzed the lineage diversity of these marker(-) cells using flow cytometry. Our study revealed that the HLA lacking occurred in more immature hematopoietic stem cells (HSCs) than HSCs with PIGA mutations. The percentage of HLA(-) granulocytes continued to increase in patients in remission off cyclosporine (CsA), suggesting that the cytotoxic T cell (CTL) attack against HSCs persists even after AA patients achieved remission not requiring CsA. On the other hand, mechanisms other than immune attack by CTLs was suspected to be involved in the survival advantage of PIGA mutated HSCs.

Academic Significance and Societal Importance of the Research Achievements

治療抵抗性の特発性再生不良性貧血に対して、40~50%の奏効が得られるエルトロンボパグ(EPAG)の登場は、再生不良性貧血診療を大きく進展させた。しかし、一部の症例に治療前には認めなかった新たな染色体異常が出現することが明らかとなり、治療開始を躊躇う例も見受けられる。そのため、EPAGの効果予測マーカーを同定することは、適切な治療を迅速に選択するためにも重要である。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (24 results)

All 2021 2020 2019 2018

All Journal Article (7 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 7 results,  Open Access: 2 results) Presentation (17 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] High-dose romiplostim accelerates hematologic recovery in patients with aplastic anemia refractory to eltrombopag2021

    • 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

    • Related Report
      2020 Annual Research Report
    • 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

    • Related Report
      2020 Annual Research Report
    • 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 anemia2021

    • 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

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Hematologic recovery induced by eltrombopag in Japanese patients with aplastic anemia refractory or intolerant to immunosuppressive therapy.2019

    • Author(s)
      Yamazaki H, Ohta K, Iida H, Imada K, Obara N, Tokumine Y, Tomiyama Y, Usuki K, Imajo K, Miyamura K, Sasaki O, Fanghong Z, Hattori T, Tajima T, Matsuda A, Nakao S.
    • Journal Title

      Int J Hematol

      Volume: 110 Issue: 2 Pages: 187-196

    • DOI

      10.1007/s12185-019-02683-1

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Prospective randomized trial comparing two doses of rabbit anti-thymocyte globulin in patients with severe aplastic anaemia.2019

    • Author(s)
      Narita A, Zhu X, Muramatsu H, Chen X, Guo Y, Yang W, Zhang J, Liu F, Jang JH, Kook H, Kim H, Usuki K, Yamazaki H, Takahashi Y, Nakao S, Wook Lee J, Kojima S
    • Journal Title

      Br J Haematol

      Volume: 187 Issue: 2 Pages: 227-237

    • DOI

      10.1111/bjh.16055

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Acquired aplastic anemia: recent advances in pathophysiology and treatment2018

    • Author(s)
      山崎宏人
    • Journal Title

      Rinsho Ketsueki

      Volume: 59 Issue: 6 Pages: 711-715

    • DOI

      10.11406/rinketsu.59.711

    • NAID

      130007393852

    • ISSN
      0485-1439, 1882-0824
    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Treatment strategy for acquired aplastic anemia2018

    • Author(s)
      山崎宏人
    • Journal Title

      Rinsho Ketsueki

      Volume: 59 Issue: 10 Pages: 1969-1978

    • DOI

      10.11406/rinketsu.59.1969

    • NAID

      130007496919

    • ISSN
      0485-1439, 1882-0824
    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Presentation] Factors affecting response to romiplostim in patients with aplastic anemia refractory to eltrombopag2020

    • Author(s)
      Hirohito Yamazaki,Kohei Hosokawa,Mikoto Tanabe,Tatsuya Imi,Naomi Sugimori,Wakana Takahashi,Keiji Aoshima,Shinji Nakao
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Infrequent somatic mutations in patients with refractory aplastic anemia treated with TPO-RAs2020

    • Author(s)
      Tatsuya Imi,Yasuhito Nannya,Kohei Hosokawa,Noriko Iwaki,Hiroyuki Takamatsu,Ken Ishiyama,Hirohito Yamazaki,Seishi Ogawa,Shinji Nakao
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] PNH-type cells are clonal or oligoclonal, even when they account for <1% of the total granulocytes2020

    • Author(s)
      Hiroki Mizumaki,Kohei Hosokawa,Ken Ishiyama,Hirohito Yamazaki,Shinji Nakao
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Selective HLA-DR loss on HSPCs in patients with CsA-dependent aplastic anemia carrying DR152020

    • Author(s)
      Noriaki Tsuji,Kohei Hosokawa,Ryota Urushihara,Mikoto Tanabe,Hiroyuki Takamatsu,Ken Ishiyama,Hirohito Yamazaki,Shinji Nakao
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Annual Research Report
  • [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 Cells2020

    • Author(s)
      Noriaki Tsuji, Kohei Hosokawa, Ryota Urushihara, Mikoto Tanabe, Hiroyuki Takamatsu, Ken Ishiyama, Hirohito Yamazaki, Shinji Nakao
    • Organizer
      The 62th ASH annual meeting
    • Related Report
      2020 Annual Research Report
    • 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 Anemia2020

    • Author(s)
      Kohei Hosokawa, Hiroki Mizumaki, Takeshi Yoroidaka, Hiroyuki Maruyama, Tatsuya Imi, Noriaki Tsuji, Ryota Urushihara, Mikoto Tanabe, Yoshitaka Zaimoku, Mai Anh Thi Nguyen, Dung Cao Tran, Ken Ishiyama, Hirohito Yamazaki, Takamasa Katagiri, Kazuyoshi Hosomichi, Atsushi Tajima, Fumihiro Azuma, Seishi Ogawa, Shinji Nakao
    • Organizer
      The 62th ASH annual meeting
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The erythropoietic reserve correlates with the response to eltrombopag in refractory aplastic anemia2019

    • Author(s)
      Ken Ishiyama, Hirohito Yamazaki, Kohei Hosokawa, Tatsuya Imi, Hiroki Mizumaki, Mikoto Tanabe, Noriaki Tsuji
    • Organizer
      第81回日本血液学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Persistent immune selection of HLA-lacking HSPCs in convalescent patients with aplastic anemia2019

    • Author(s)
      Noriaki Tsuji, Kohei Hosokawa, Mikoto Tanabe, Takeshi Yoroidaka, Hiroki Mizumaki, Hiroyuki Takamatsu, Ken Ishiyama, Hirohito Yamazaki, Shinji Nakao
    • Organizer
      第81回日本血液学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] A GPI-anchored protein CD109 protects TF-1 cells from undergoing differentiation induced by TGF-β2019

    • Author(s)
      Mikoto Tanabe, Noriharu Nakagawa, Kohei Hosokawa, Thinguyen Maianh, Espinoza Luis, Kana Maruyama, Takamasa Katagiri, Hirohito Yamazaki, Shinji Nakao
    • Organizer
      第81回日本血液学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] The high NK cell count at diagnosis predicts a good response to IST in aplastic anemia2019

    • Author(s)
      Atsushi Narita, Hideki Muramatsu, Yinyan Xu, Motoharu Hamada, Daisuke Ichikawa, Eri Nishikawa, Nozomu Kawashima, Yusuke Okuno, Nobuhiro Nishio, Hirohito Yamazaki, Shinji Nakao, Seiji Kojima, Yoshiyuki Takahashi
    • Organizer
      第81回日本血液学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] A GPI-Anchored Protein, CD109, Protects Hematopoietic Progenitor Cells from Erythroid Differentiation Induced By TGF-β2019

    • Author(s)
      Tanabe Mikoto, Nguyen Hoang Maianh, Kohei Hosokawa, Noriharu Nakagawa, Luis Espinoza, Hirohito Yamazaki, Shinji Nakao
    • Organizer
      61st ASH Annual meeting(第61回アメリカ血液学会)
    • Related Report
      2019 Research-status Report
  • [Presentation] Reticulocyte counts over 30,000/μL predict a good response to eltrombopag in refractory AA2018

    • Author(s)
      Keijiro Sato, Ken Ishiyama, Masahisa Arahata, Kohei Hosokawa, Yukio Kondo, Hirohito Yamazaki, Shinji Nakao
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Limited class I HLAs are involved in the auto-antigen presentation in acquired aplastic anemia2018

    • Author(s)
      Mikoto Tanabe, Hiroki Mizumaki, Tatsuya Imi, Takeshi Yoroidaka, Noriharu Nakagawa, Ken Ishiyama, Hirohito Yamazaki, Yoshiraka Zaimoku, Takamasa Katagiri, Kazuyoshi Hosomichi, Atsushi Tajima, Shinji Nakao
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Familial acquired aplastic anemia diagnosed by aberrant leukocytes that lacked common HLA alleles2018

    • Author(s)
      Tatsuya Imi, Ryosuke Ogawa, Kazuyoshi Hosomichi, Hiroki Mizumaki, Noriharu Nakagawa, Takeshi Yoroidaka, Mikoto Tanabe, Noriaki Tsuji, Kohei Hosokawa, Hiroyuki Takamatsu, Ken Ishiyama, Yukio Kondo, Hirohito Yamazaki, Atsushi Tajima, Shinji Nakao
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Response to IST in PNH(+) BMF patients with a history of chemo- or radiotherapy2018

    • Author(s)
      Noriharu Nakagawa, Mikoto Tanabe, Ishikazu Mizuno, Satoshi Morishige, Shuji Matsuzawa, Takahiko Ito, Masahiko Sumi, Nobuyuki Takayama, Ken Ishiyama, Hirohito Yamazaki, Shinji Nakao
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] 再生不良性貧血の治療戦略2018

    • Author(s)
      山崎宏人
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] The depletion of TGF-β co-receptor CD109 induces erythroid differentiation of TF-1 cells: a model of preferential commitment of PIGA-mutated hematopoietic stem cells in immune-mediated bone marrow failure.2018

    • Author(s)
      Tanabe Mikoto, Noriharu Nakagawa, Kohei Hosokawa, Luis Espinoza, Kana Maruyama, Takamasa Katagiri, Hirohito Yamazaki, Shinji Nakao
    • Organizer
      The 60th ASH annual meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2022-01-27  

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