Mutational profiles of T cells in bone marrro failure syndrome as clinical markers

• Project/Area Number: 20K08709
• 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: Shinshu University
• Principal Investigator: Ishida Fumihiro 信州大学, 学術研究院保健学系, 教授 (80311695)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥520,000 (Direct Cost: ¥400,000、Indirect Cost: ¥120,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 赤芽球癆 / 遺伝子変異 / 貧血 / クローン性造血 / STAT3 / T細胞 / エピゲノム修飾 / 骨髄不全症候群 / 体細胞変異 / bone marrow failure / pure red cell aplasia / T cell

Outline of Research at the Start

骨髄不全症候群(BMF)は後天性の骨髄造血障害により血球減少を来す難治性の血液疾患群である。BMFは主として免疫抑制療法で治療されるが、免疫病態の詳細は不明な点も多い。
本研究ではBMF症例のT細胞の遺伝子を網羅的に解析し、T細胞の遺伝子変異像と臨床像の関係を調べる。そして、BMFについて、より適切な分類・診断・治療選択に有用となるT細胞の遺伝子変異像をマーカーとした新規指標を確立する。

Outline of Final Research Achievements

Bone marrow failure syndrome (BMF) is defined as chronic cytopenia due to acquired impaired hematopoiesis. Cellular immune dysfunction has been a main cause of BMF, especially in aplastic anemia (AA) and pure red cell aplasia (PRCA), although the details are still uncertain.
We performed whole exome sequencing anaysis and target sequencing on peripheral blood from patients with PRCA in order to elucidate molecular pathophysiology of BMF including PRCA. In addition to well recognized STAT3 mutations, a set of genes, including clonal hematopoiesis-related genes such as epigenetic modifier genes, were frequently mutated in PRCA, which were with a different pattern from AA. Several gene mutations were associated with specific subtypes of PRCA and/or relapse after immunosuppressive therapies.
Mutational gene analyses in PRCA would be helpful for establishing better classification and diagnostic criteria of BMF including PRCA and also for clinical decision making on PRCA.

Academic Significance and Societal Importance of the Research Achievements

骨髄不全症候群は後天性に造血が障害されて貧血などの血球減少を呈し慢性に経過し、しばしば難治性である。骨髄不全症候群の多くは赤芽球癆を含め厚生労働省の指定難病に指定されている。赤芽球癆には多くの病型があり、初期治療で免疫抑制療法が奏効するものの、再燃や不応例も一定の割合で生じている。今回の研究により、赤芽球癆の遺伝子変異像を特定したことで赤芽球癆の病態のより深い理解につながり、赤芽球癆を含めた骨髄不全症候群の適切な診断や病型分類に役立てることができる。また、赤芽球癆の初期治療およびその後の治療法を選択に有用である可能性がある。

Research Products

• [Int'l Joint Research] ヘルシンキ大学(フィンランド)
• [Int'l Joint Research] UNIVERSITY OF HELSINKI(フィンランド)
• [Int'l Joint Research] UNIVERSITY OF PADOVA(イタリア)
• [Int'l Joint Research] UNIVERSITY OF VIRGINIA/CLEAVELAND CLINIC(米国)
• [Journal Article] Somatic mutations in acquired pure red cell aplasia (2022)
  • Author(s): Kawakami Toru、Nakazawa Hideyuki、Ishida Fumihiro
  • Journal Title: Seminars in Hematology Volume: 59 Issue: 3 Pages: 131-136
  • DOI: 10.1053/j.seminhematol.2022.07.001
  • Peer Reviewed
• [Journal Article] Incidence of Acquired Pure Red Cell Aplasia: A Nationwide Epidemiologic Analysis with Two Registry Databases in Japan. (2022)
  • Author(s): Nakazawa H, Sakai K, Ohta A, Fujishima N, Matsuda A, Hosokawa K, Nakamura F, Nakao S, Mitani K, Ishida F
  • Journal Title: Blood Advances Volume: 6 Issue: 24 Pages: 6282-6290
  • DOI: 10.1182/bloodadvances.2021006486
  • Peer Reviewed / Open Access
• [Journal Article] Anti-COX-2 autoantibody is a novel biomarker of immune aplastic anemia (2022)
  • Author(s): Kelkka Tiina、Tyster Mikko、Lundgren Sofie、Feng Xingmin、Kerr Cassandra、Hosokawa Kohei、Huuhtanen Jani、Keranen Mikko、Patel Bhavisha、Kawakami Toruら
  • Journal Title: Leukemia Volume: 36 Issue: 9 Pages: 2317-2327
  • DOI: 10.1038/s41375-022-01654-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] T cell clonal expansion and STAT3 mutations: a characteristic feature of acquired chronic T cell-mediated pure red cell aplasia (2022)
  • Author(s): Kawakami Fumihiro、Kawakami Toru、Yamane Taku、Maruyama Masae、Kobayashi Jun、Nishina Sayaka、Sakai Hitoshi、Higuchi Yumiko、Hamanaka Kazutoshi、Hirokawa Makoto、Nakao Shinji、Nakazawa Hideyuki、Ishida Fumihiro
  • Journal Title: International Journal of Hematology Volume: ー Issue: 6 Pages: 816-825
  • DOI: 10.1007/s12185-022-03310-2
  • Peer Reviewed / Open Access
• [Journal Article] Identification of novel STAT5B mutations and characterization of TCRβ signatures in CD4+ T-cell large granular lymphocyte leukemia (2022)
  • Author(s): Bhattacharya D, Teramo A, Gasparini VR, Huuhtanen J, Kim D, Theodoropoulos J, Schiavoni G, Barila G, Vicenzetto C, Calabretto G, Facco M, Kawakami T, Nakazawa H, Falini B, Tiacci E, Ishida F, Semenzato G, Kelkka T, Zambello R, Mustjoki S
  • Journal Title: Blood Cancer J Volume: 12 Issue: 2 Pages: 31-31
  • DOI: 10.1038/s41408-022-00630-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serum sphiongomyelin species profile is altered in hematological malignancies. (2021)
  • Author(s): Hori A, Ishida F, Nakazawa H, Yamaura M, Morita S, Uehara T, Honda T, Hidaka H.
  • Journal Title: Clinica Chimica Acta. Volume: 514 Pages: 29-33
  • DOI: 10.1016/j.cca.2020.11.024
  • Peer Reviewed
• [Journal Article] Clonal hematopoiesis in adult pure red cell aplasia (2021)
  • Author(s): Fujishima N、Kohmaru J、Koyota S、Kuba K、Saga T、Omokawa A、Moritoki Y、Ueki S、Ishida F、Nakao S、Matsuda A、Ohta A、Tohyama K、Yamasaki H、Usuki K、Nakashima Y、Sato S、Miyazaki Y、Nannya Y、Ogawa S、Sawada K、Mitani K、Hirokawa M
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 2253-2253
  • DOI: 10.1038/s41598-021-81890-5
  • Peer Reviewed / Open Access
• [Journal Article] High frequency of STAT3 gene mutations in T‐cell receptor (TCR)γδ‐type T‐cell large granular lymphocytic leukaemia: implications for molecular diagnostics (2020)
  • Author(s): Yamane T、Kawakami T、Sekiguchi N、Kobayashi J、Ueki T、Kobayashi H、Kawakami F、Nishina S、Sakai H、Oshimi K、Higuchi Y、Nakazawa H、Ishida F
  • Journal Title: British Journal of Haematology Volume: 190 Issue: 5 Pages: 46-51
  • DOI: 10.1111/bjh.16820
  • Peer Reviewed
• [Journal Article] Primary thyroid T‐cell lymphoma with leukemic manifestation (2020)
  • Author(s): Kawakami T、Nakazawa H、Ishida F
  • Journal Title: eJHaem Volume: 1 Issue: 1 Pages: 18-18
  • DOI: 10.1002/jha2.31
  • Peer Reviewed / Open Access
• [Journal Article] T(o) be, or (not) to B, or both? Somatically mutated clonal T cells in common variable immunodeficiency and related immunodeficiencies (2020)
  • Author(s): Ishida F、Nakazawa H
  • Journal Title: Haematologica Volume: 105 Issue: 12 Pages: 2702-2703
  • DOI: 10.3324/haematol.2020.261982
  • Open Access
• [Journal Article] Allogeneic stem cell transplantation for patients with aggressive NK-cell leukemia (2020)
  • Author(s): Fujimoto A、Ishida F、Izutsu K、Yamasaki S、Chihara D、Suzumiya J、Mitsui T、Doki N、Sakai H、Kobayashi H、Kanda J、Fukuda T、Atsuta Y、Suzuki R
  • Journal Title: Bone Marrow Transplantation Volume: 56 Issue: 2 Pages: 347-356
  • DOI: 10.1038/s41409-020-01009-8
  • Peer Reviewed
• [Journal Article] 後天性赤芽球癆の病態と治療研究の進歩 (2020)
  • Author(s): 石田文宏
  • Journal Title: 臨床血液 Volume: 61 Pages: 92-98
  • NAID: 130007937115
  • Peer Reviewed
• [Presentation] Molecular mechanisms of acquired pure red cell aplasia. (2022)
  • Author(s): 石田文宏
  • Organizer: 第84回日本血液学会学術集会
  • Invited
• [Presentation] Mutational profiles of STAT3 and clonal hematopoiesis-related genes characteristic of acquired PRCA (2022)
  • Author(s): 川上徹、山根拓、川上史裕、丸山正恵、井田夏実、水野裕雅、朝倉亜美、仁科さやか、酒井均、樋口由美子、中澤英之、石田文宏
  • Organizer: 第84回日本血液学会学術集会
• [Presentation] Clinical and pathophysiological features of acquired pure red cell aplasia (2021)
  • Author(s): Fumihiro Ishida
  • Organizer: 第83回日本血液学会学術集会
  • Invited
• [Presentation] T-gamma/delta large granular lymphocyte leukemia identified a subset of patients with more symptomatic disease: Analysis of a collaborative international cohort of 130 patients (2020)
  • Author(s): Barila G, Teramo A, Cheson H, Calabretto G, Chahal J, Vienzetto C, Almeida J, Shemo B, Min S, Gasparini VR, Pavan L, Oshimi K, Sokol L, Ishida F, Lamy T, Orfao A, Morice WG, Loughran T, Semenzato G, Zambello R.
  • Organizer: 25th Congress of the European Hematology Association
  • Int'l Joint Research
• [Presentation] Clonal T cells and STAT3 mutations in acquired pure red cell aplasia (2020)
  • Author(s): Kawakami F, Kawakami T, Yamane T, Kobayashi J, Nishina S, Sakai H, Higuchi Y, Nakao S, Hirokawa M, Nakazawa H, Ishida F
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Specific immunophenotype of CD8+T cells in patients with refractory pure red cell aplasia (2020)
  • Author(s): Kawakami T, Yamane T, Kawakami F, Kobayashi J, Sekiguchi N, Nishina S, Sakai H, Higuchi Y, Nakazawa H, Ishida F
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Recent progress in the diagnosis and management of acquired pure red cell aplasia. (2020)
  • Author(s): Ishida F
  • Organizer: 第82回日本血液学会学術集会
  • Invited
• [Presentation] CD5 down-regulation unique to STAT3-mutated CD8+T cells in PRCA patients associated with T-LGLL. (2020)
  • Author(s): Tanabe M, Hosokawa K, Imi T, Nakagawa N, Kawakami T, Ishida F, Nakazawa H, Nakao S.
  • Organizer: 第82回日本血液学会学術集会