Identification of T cell pathway causing the acquired aplastic anemia

• Project/Area Number: 17K16184
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Kanazawa University
• Principal Investigator: Hosokawa Kohei 金沢大学, 附属病院, 助教 (10786239)
• Research Collaborator: Hosomichi Kazuyoshi ; Young Neal. S.
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 再生不良性貧血 / トランスクリプトーム解析 / 造血不全 / 免疫学

Outline of Final Research Achievements

To identify aberrant molecular mechanisms involved in immune targeting of hematopoietic stem cells in bone marrow, we applied RNA-seq to examine the transcriptome of T cell subsets from AA/PNH patients and healthy control subjects. Differentially expressed gene analysis in four different T cell subsets from PNH and healthy control subjects showed distinct transcriptional profiles, depending on the T cell subsets. By pathway analysis, we identified novel signaling pathways in T cell subsets, including increased gene expression involved in TNFR, IGF1, NOTCH, AP-1, and ATF2 pathways. Dysregulation of several candidate genes (JUN, TNFAIP3, TOB1, GIMAP4, GIMAP6, TRMT112, NR4A2, CD69, and TNFSF8) was validated by quantitative real-time RT-PCR and flow cytometry.

Academic Significance and Societal Importance of the Research Achievements

骨髄不全型PNHにおいてT細胞を正または負に制御するパスウェイや遺伝子が同定されたことから、これらの遺伝子を標的とした治療への応用が期待される。

Research Products

• [Journal Article] Escape hematopoiesis by HLA-B5401-lacking hematopoietic stem progenitor cells in men with acquired aplastic anemia. (2019)
  • Author(s): Mahmoud I. Elbadry、Mizumaki Hiroki、Hosokawa Kohei、J. Luis Espinoza、Nakagawa Noriharu、Chonabayashi Kazuhisa、Yoshida Yoshinori、Katagiri Takamasa、Hosomichi Kazuyoshi、Zaimoku Yoshitaka、Imi Tatsuya、Mai Anh Thi Nguyen、Fujii Youichi、Tajima Atsushi、Ogawa Seishi、Takenaka Katsuto、Akashi Koichi、Nakao Shinji
  • Journal Title: Haematologica Volume: 印刷中 Issue: 10 Pages: 210856-210856
  • DOI: 10.3324/haematol.2018.210856
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Establishment of a flow cytometry assay for detecting paroxysmal nocturnal hemoglobinuria-type cells specific to patients with bone marrow failure (2018)
  • Author(s): Hosokawa Kohei、Sugimori Chiharu、Ishiyama Ken、Takamatsu Hiroyuki、Noji Hideyoshi、Shichishima Tsutomu、Obara Naoshi、Chiba Shigeru、Ninomiya Haruhiko、Shirasugi Yukari、Nakamura Yoshihiko、Ando Kiyoshi、Ueda Yasutaka、Yonemura Yuji、Kawaguchi Tatsuya、Nishimura Jun-ichi、Kanakura Yuzuru、Nakao Shinji
  • Journal Title: Annals of Hematology Volume: 97 Issue: 12 Pages: 2289-2297
  • DOI: 10.1007/s00277-018-3443-1
  • Peer Reviewed
• [Journal Article] Abnormal RNA splicing and genomic instability after induction of DNMT3A mutations by CRISPR/Cas9 gene editing (2018)
  • Author(s): Banaszak LG, Giudice V, Zhao X, Wu Z, Gao S, Hosokawa K, Keyvanfar K, Townsley DM, Gutierrez-Rodrigues F, Fernandez Ibanez MDP, Kajigaya S, Young NS
  • Journal Title: Blood cells, molecules & diseases Volume: 69 Pages: 10-22
  • DOI: 10.1016/j.bcmd.2017.12.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] T Cell Transcriptomes from Paroxysmal Nocturnal Hemoglobinuria Patients Reveal Novel Signaling Pathways. (2017)
  • Author(s): Hosokawa K, Kajigaya S, Keyvanfar K, Qiao W, Xie Y, Townsley DM, Feng X, Young NS.
  • Journal Title: The Journal of Immunology Volume: 199(2) Issue: 2 Pages: 477-488
  • DOI: 10.4049/jimmunol.1601299
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 免疫性造血不全における変異造血幹細胞によるエスケープ造血 (2018)
  • Author(s): 細川晃平、中尾眞二
  • Organizer: 第80回 日本血液学会学会学術集会
  • Invited
• [Presentation] Escape Hematopoiesis By HLA-B5401-Lacking Hematopoietic Stem Progenitor Cells in Male Patients with Acquired Aplastic Anemia (2018)
  • Author(s): Kohei Hosokawa, Mahmoud Ibrahim Elbadry, Hiroki Mizumaki, Luis Espinoza, Noriharu Nakagawa, Kazuhisa Chonabayashi, Yoshinori Yoshida, Takamasa Katagiri, Yoshitaka Zaimoku, Tatsuya Imi, Nguyen Thi Mai Anh, Yoichi Fujii, Seishi Ogawa, Katsuto Takenaka, Koichi Akashi and Shinji Nakao
  • Organizer: 2018 ASH annual meeting
  • Int'l Joint Research
• [Presentation] Bystander Proliferation of Piga-Mutated Hematopoietic Progenitor Cells in Acquired Aplastic Anemia Patients Possessing HLA Class I Allele-Lacking Leukocytes (2018)
  • Author(s): Takeshi Yoroidaka, Kohei Hosokawa, Tatsuya Imi, Takamasa Katagiri, Fumihiro Azuma and Shinji Nakao
  • Organizer: 2018 ASH annual meeting
  • Int'l Joint Research
• [Presentation] Loss-of-Function Mutations in HLA-Class I Alleles in Acquire Aplastic Anemia: Evidence for the Involvement of Limited Class I Alleles in the Auto-Antigen Presentation of Aplastic Anemia (2018)
  • Author(s): Hiroki Mizumaki, Kazuyoshi Hosomichi, Tanabe Mikoto, Takeshi Yoroidaka, Tatsuya Imi, Yoshitaka Zaimoku, Kohei Hosokawa, Takamasa Katagiri, Hiroyuki Takamatsu, Tatsuhiko Ozawa, Fumihiro Azuma, Hiroyuki Kishi, Atsushi Tajima and Shinji Nakao
  • Organizer: 2018 ASH annual meeting
  • Int'l Joint Research
• [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 and Shinji Nakao
  • Organizer: 2018 ASH annual meeting
  • Int'l Joint Research
• [Book] Congenital and Acquired Bone Marrow Failure (2017)
  • Author(s): Hosokawa K, Scheinberg P, and Young, N.S.
  • Total Pages: 274
  • Publisher: Elsevier
  • ISBN: 9780128041529