Role of STAP proteins in allogeneic hematopoietic stem cell transplantation

• Project/Area Number: 19K08815
• 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: Osaka University
• Principal Investigator: Saitoh Hideaki 大阪大学, 医学部附属病院, 医員 (50815496)
• Co-Investigator(Kenkyū-buntansha): 一井 倫子 大阪大学, 医学系研究科, 助教 (30633010) ; 柴山 浩彦 大阪大学, 医学系研究科, 招へい教授 (60346202) ; 戸田 淳 大阪大学, 医学部附属病院, 医員 (90770834)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 同種造血幹細胞移植 / GVHD / 同種移植 / リンパ球 / STAP / STAP蛋白 / 胸腺再生 / 免疫再構築

Outline of Research at the Start

Signal-transducing adaptor protein(STAP)蛋白ファミリーは、リン脂質結合モチーフであるPleckstrin homology (PH)ドメイン、リン酸化チロシンとの親和性が知られるSrc homology (SH)2ドメインに類似した構造を有するアダプター蛋白である。申請者らは以前より、STAP蛋白が炎症・免疫系シグナルを調整することを報告してきた。本研究では、STAP蛋白が同種造血幹細胞移植後の免疫再構築とその後の同種免疫応答において果たす役割について明らかにする。本研究の研究成果が移植後晩期合併症に対する新たな治療アプローチにつながる事が期待できる。

Outline of Final Research Achievements

Signal-transducing adaptor protein (STAP) family regulates various intracellular signaling pathways with a pleckstrin homology domain in the N-terminal region and SRC-homology 2-like domain. Following the elucidation of the effects of STAPs on terminally differentiated immune cells, such as macrophages, T cells, mast cells, and basophils, recent findings have shown the critical roles of STAP-2 in B cell progenitor cells in marrow under hematopoietic stress and STAP-1 and -2 in BCR-ABL-transduced leukemogenesis. In this study, we evaluated the effects of STAPs on immune-reconstitution and immune responses after allogeneic hematopoietic stem cell transplantation.

Academic Significance and Societal Importance of the Research Achievements

同種造血幹細胞移植は、難治性白血病や重症の造血不全疾患などで唯一治癒が期待できる治療法であるが、移植後のGVHDや免疫不全のよる易感染性の制御が難しく、未だに高い致死リスクが存在する。本研究は生体の免疫再構築機構と移植後のGVHD発症にSTAP-2が作用する事を明らかにし、治療標的となる可能性を示した。

Research Products

• [Journal Article] Graft-versus-host disease develops in mice transplanted with lymphocyte-depleted bone marrow cells from signal-transducing adaptor protein-2 transgenic mice (2021)
  • Author(s): Saito H, Ichii M, Toda J, Kitai Y, Muromoto R, Kashiwakura JI, Saitoh K, Tanimura A, Yokota T, Shibayama H, Matsuda T, Oritani K, Kanakura Y, Hosen N.
  • Journal Title: Biochem Biophys Res Commun . Volume: 537 Pages: 118-124
  • DOI: 10.1016/j.bbrc.2020.12.080
  • Peer Reviewed / Open Access
• [Journal Article] High numbers of programmed cell death-1-positive tumor infiltrating lymphocytes correlate with early onset of post-transplant lymphoproliferative disorder (2021)
  • Author(s): Saito Hideaki、Miyoshi Hiroaki、Shibayama Hirohiko、Toda Jun、Kusakabe Shinsuke、Ichii Michiko、Fujita Jiro、Fukushima Kentaro、Maeda Tetsuo、Mizuki Masao、Oritani Kenji、Seto Masao、Yokota Takafumi、Kanakura Yuzuru、Hosen Naoki、Ohshima Koichi
  • Journal Title: International Journal of Hematology Volume: - Issue: 1 Pages: 53-64
  • DOI: 10.1007/s12185-021-03129-3
  • Peer Reviewed
• [Journal Article] Signal-transducing adaptor protein-2 delays recovery of B lineage lymphocytes during hematopoietic stress (2020)
  • Author(s): Ichii Michiko、Oritani Kenji、Toda Jun、Saito Hideaki、Shi Henyun、Shibayama Hirohiko、Motooka Daisuke、Kitai Yuichi、Muromoto Ryuta、Kashiwakura Jun-ichi、Saitoh Kodai、Okuzaki Daisuke、Matsuda Tadashi、Kanakura Yuzuru
  • Journal Title: Haematologica Volume: in press Issue: 2 Pages: 225573-225573
  • DOI: 10.3324/haematol.2019.225573
  • Peer Reviewed / Open Access
• [Presentation] Signal transducing adaptor protein (STAP)-2 accelerates graft-versus-host-disease (2020)
  • Author(s): Hideaki Saito，Michiko Ichii，Jun Toda，Yuichi Kitai，Ryuta Muromoto，Junichi Kashiwakura，Kodai Saitoh，Takafumi Yokota，Hirohiko Shibayama，Tadashi Matsuda，Kenji Oritani，Yuzuru Kanakura，Naoki Hosen.
  • Organizer: 第82回日本血液学会学術集会・総会