Role of NKG2D immunity in myelodysplastice syndrome

• Project/Area Number: 19K08821
• 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: Wakayama Medical University
• Principal Investigator: Sonoki Takashi 和歌山県立医科大学, 医学部, 教授 (30382336)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 骨髄異形成症候群 / NKG2D免疫 / 自己炎症性腸疾患 / NKG2D介在免疫 / 骨髄不全症候群 / LIG4変異 / LIG4遺伝子変異

Outline of Research at the Start

申請者らは７９名の骨髄不全（BFS）患者を対象に血清中の可溶性NKG2Dリガンド(sNKG2DL)を測定し約５割の患者がsNKG2DL陽性で、sNKG2DL陽性と血球減少に相関があることを見つけた。本研究では検討数を増やしMDS診療におけるsNKG2DLの臨床的意義を確立する。一方、申請者らは若年発症MDS患者にLIG4(DNA ligase IV)遺伝子の新規変異を見つけた。本患者のLIG4変異を模したlig4変異マウスを作成したところ、骨髄細胞密度低下・白血球数低下・MDS類似形態異常を示す白血球を生じた。このマウスを使い、MDS病態形成とNKG2D免疫との関連を調べる。

Outline of Final Research Achievements

(1) Serum sNKG2DLs levels were measured in patients with myelodysplastic syndrome (MDS) and healthy subjects. Serum sNKG2DLs levels were lower in MDS patients than in healthy subjects. Previous reports have shown that serum sNKG2DLs were higher in aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) patients with bone marrow failure than in normal subjects. These results suggest that serum sNKG2DL levels may be useful in differentiating MDS from AA and PNH. (2) We identified a new genetic mutation in a patient with MDS and created a mouse model. These mice developed hematopoietic failure and enteritis. We confirmed that abnormal blood cells are important in the development of enteritis.

Academic Significance and Societal Importance of the Research Achievements

骨髄異形成症候群（MDS）は、高齢者に好発する難治性血液疾患で、血球数低下をきたし、時に自己炎症性疾患を併発する。MDSの血球数低下には免疫介在性細胞障害が関与している。私達はMDSにおけるNK免疫の関与を調べるために、患者血清のNKG2Dリガンド値を調べた。その結果、MDS患者の血清NKG2Dリガンド値は健常人よりも低値であることがわかった。この結果は血球数低下をきたす類似疾患（再生不良性貧血や発作性夜間血色素尿症）と異なっており、鑑別診断に有用である。また、MDSのモデルマウスを作成したところ、血球数低下の他、自己炎症性腸炎を発症した。このマウスはMDSの免疫病態を調べる上で有用である。

Research Products

• [Journal Article] Severe aplastic anemia after COVID-19 mRNA vaccination: Causality or coincidence? (2022)
  • Author(s): Tabata Shotaro、Hosoi Hiroki、Murata Shogo、Takeda Satomi、Mushino Toshiki、Sonoki Takashi
  • Journal Title: Journal of Autoimmunity Volume: 126 Pages: 102782-102782
  • DOI: 10.1016/j.jaut.2021.102782
  • Peer Reviewed
• [Journal Article] Composite Epstein-Barr Virus-associated T-lymphoblastic and Peripheral T-cell Lymphomas: A Clonal Study (2021)
  • Author(s): Hosoi Hiroki、Mushino Toshiki、Nakashima Kazutaka、Kuriyama Kodai、Tamura Shinobu、Murata Shogo、Imadome Ken-Ichi、Ohshima Koichi、Sonoki Takashi
  • Journal Title: Internal Medicine Volume: 60 Issue: 13 Pages: 2119-2123
  • DOI: 10.2169/internalmedicine.6572-20
  • NAID: 130008060437
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-07-01
  • Peer Reviewed / Open Access
• [Journal Article] Management of warm autoimmune hemolytic anemia related to band 3-positive colon carcinoma (2021)
  • Author(s): Matsuyama Yoriko、Hosoi Hiroki、Horitani Ryosuke、Kawamoto Shinichiro、Hashimoto Tadayuki、Kimura Masatomo、Nakai Hiroaki、Mushino Toshiki、Sonoki Takashi
  • Journal Title: Annals of Hematology Volume: - Issue: 6 Pages: 1343-1344
  • DOI: 10.1007/s00277-021-04714-6
  • Peer Reviewed
• [Journal Article] Super-enhancers for RUNX3 are required for cell proliferation in EBV-infected B cell lines (2021)
  • Author(s): Hosoi Hiroki、Niibori-Nambu Akiko、Nah Giselle Sek Suan、Bahirvani Avinash Govind、Mok Michelle Meng Huang、Sanda Takaomi、Kumar Alan Prem、Tenen Daniel G.、Ito Yoshiaki、Sonoki Takashi、Osato Motomi
  • Journal Title: Gene Volume: 774 Pages: 145421-145421
  • DOI: 10.1016/j.gene.2021.145421
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of bone marrow aspiration clots for evaluating cellularity: comparison of clots, biopsies, and smears (2021)
  • Author(s): Tanaka Ken、Hosoi Hiroki、Kodama Rieko、Tabata Shotaro、Hiroi Takayuki、Kida Yohei、Mushino Toshiki、Murata Shogo、Tamura Shinobu、Ikeda Takeshi、Sonoki Takashi
  • Journal Title: Annals of Hematology Volume: 100 Issue: 11 Pages: 2843-2844
  • DOI: 10.1007/s00277-021-04596-8
  • Peer Reviewed
• [Journal Article] Dose-adjusted high-dose chemotherapy with autologous stem cell transplantation for elderly (70 years old) lymphoma patients (2021)
  • Author(s): Hosoi Hiroki、Murata Shogo、Mushino Toshiki、Tamura Shinobu、Sonoki Takashi
  • Journal Title: Annals of Hematology Volume: - Issue: 1 Pages: 205-207
  • DOI: 10.1007/s00277-020-04373-z
  • Peer Reviewed
• [Journal Article] Targeting Adaptive IRE1α Signaling and PLK2 in Multiple Myeloma: Possible Anti-Tumor Mechanisms of KIRA8 and Nilotinib. (2020)
  • Author(s): Yamashita Y, Morita S, Hosoi H, Kobata H, Kishimoto S, Ishibashi T, Mishima H, Kinoshita A, Backes BJ, Yoshiura KI, Papa FR, Sonoki T, Tamura S
  • Journal Title: Int J Mol Sci. Volume: Aug 31;21(17) Issue: 17 Pages: 6314-6314
  • DOI: 10.3390/ijms21176314
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Soluble NKG2D Ligands Are Potential Biomarkers and Sentinels of Immune-Mediated Bone Marrow Injury in Bone Marrow Failure Syndromes. (2020)
  • Author(s): Murata S, Mushino T, Hosoi H, Kuriyama K, Nishikawa A, Nagakura S, Horikawa K, Yonemura Y, Nakakuma H, Sonoki T, Hanaoka N.
  • Journal Title: Acta Haematol. Volume: 143(1) Issue: 1 Pages: 33-39
  • DOI: 10.1159/000500657
  • Peer Reviewed / Open Access
• [Journal Article] PKN1 kinase-negative knock-in mice develop splenomegaly and leukopenia at advanced age without obvious autoimmune-like phenotypes. (2019)
  • Author(s): Siddique SM, Kubouchi K, Shinmichi Y, Sawada N, Sugiura R, Itoh Y, Uehara S, Nishimura K, Okamura S, Ohsaki H, Kamoshida S, Yamashita Y, Tamura S, Sonoki T, Matsuoka H, Itoh T, Mukai H.
  • Journal Title: Sci Rep. Volume: 27;9(1) Issue: 1 Pages: 13977-13993
  • DOI: 10.1038/s41598-019-50419-2
  • NAID: 120006733136
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a novel CCDC22 mutation in a patient with severe Epstein?Barr virus-associated hemophagocytic lymphohistiocytosis and aggressive natural killer cell leukemia (2019)
  • Author(s): Yamashita Y, Nishikawa A, Iwahashi Y, Fujimoto M, Sasaki I, Mishima H, Kinoshita A, Hemmi H, Kanazawa N, Ohshima K, Imadome KI, Murata SI、Yoshiura KI, Kaisho T, Sonoki T, Tamura S
  • Journal Title: International Journal of Hematology Volume: 印刷中 Issue: 6 Pages: 744-750
  • DOI: 10.1007/s12185-019-02595-0
  • Peer Reviewed / Open Access
• [Presentation] Reduction of IgG level after R-chemo might be a predictive factor for prognosis in B-cell lymphoma (2021)
  • Author(s): Shotaro Tabata, Hiroki Hosoi, Ken Tanaka, Takayuki Hiroi, Yohei Kida, Toshiki Mushino, Shogo Murata, Shinobu Tamura, Takeshi Ikeda, Takashi Sonoki
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Clinical impact of CD30 expression in adult T cell leukemia/lymphoma:Wakayama retrospective study (2021)
  • Author(s): Kikuaki Yoshida, Toshiki Mushino, Hideki Kosako, Yoshiaki Huruya, Ken Tanaka, Takayuki Hiroi, Yoshikazu Hori, Masaya Morimoto, Yusuke Yamashita, Hiroki Hosoi, Shogo Murata, Rin Sakaguchi, Akinori Nishikawa, Hiroaki Miyoshi, Koichi Ohshima, Takashi Sonoki
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Primary myelofibrosis showing Sweet’s syndrome, progressive dysplasia, and mutational evolution (2021)
  • Author(s): Hideki Kosako, Hiroki Hosoi, Minako Tanaka, Ryuta Iwamoto, Yoshifumi Iwahashi, Yuki Mori, Ikuro Tanigawa, Ayaka Sakaki, Satomi Takeda, Yuma Yokoya, Shotaro Tabata, Kikuaki Yoshida,, Masatoshi Jinnin, Takashi Sonoki
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Long-term follow-up of DLBCL patients aged over 80 years treated with reduced dose R-THP-COP (2021)
  • Author(s): Takayuki Hiroi, Hiroki Hosoi, Kodai Kuriyama, Masaya Morimoto, Shogo Murata, Toshiki Mushino, Shinobu Tamura, Takashi Sonoki
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Role of BM aspiration clots: comparison of clots, biopsies, and smears for evaluating BM cellularity (2021)
  • Author(s): Ken Tanaka, Hiroki Hosoi, Rieko Kodama, Shotaro Tabata, Takayuki Hiroi, Yohei Kida, Toshiki Mushino, Shogo Murata, Shinobu Tamura, Takeshi Ikeda, Takashi Sonoki
  • Organizer: 第83回日本血液学会学術集会
• [Presentation] Pathological characterization of Th1-mediated colitis based on primary immunodeficiency (2020)
  • Author(s): Tamura S, Yamashita Y, Orimo T, Iwabuchi S, Nakashima K, Sasaki I, Hemmi H, Hashimoto S, Ohshima K, Kaisho T, Sonoki T
  • Organizer: 日本血液学会総会
• [Presentation] ERストレスセンサー新規阻害薬KIRA8はIRE1αXBP1/PLK2 axisを制御することで抗骨髄腫作用を誘導する (2020)
  • Author(s): 山下友佑、森田修平、細井裕樹、赤水尚史、園木孝志、田村志宣
  • Organizer: 日本血液学会総会
• [Presentation] DNA損傷修復障害モデルマウスを用いた腸管免疫寛容破綻の病態解明 (2019)
  • Author(s): 田村志宣, 山下友佑, 折茂貴是, 福田有里, 小笹俊哉 , 中嶋一貴, 金澤伸雄, 邊見弘明, 大島孝一, 改正恒康, 園木孝志
  • Organizer: 第47回日本臨床免疫学会総会