Mechanism of myelofibrosis and extramedullary hematopoiesis by fibrocytes

• Project/Area Number: 18K08344
• 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: National Defense Medical College
• Principal Investigator: Kimura Fumihiko 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 内科学, 教授 (50536216)
• Co-Investigator(Kenkyū-buntansha): 大澤 有紀子 防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 内科学, 助教 (00816928) ; 佐藤 謙 帝京大学, 医学部, 教授 (20531297)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 骨髄増殖性腫瘍 / 骨髄線維症 / 線維細胞 / CHI3L1 / IL-1レセプターアンタゴニスト / Chitinase-3-like 1

Outline of Final Research Achievements

Myeloproliferative neoplasms, blood cancer with excess production of red blood cells, white blood cells, and platelets, have a clinical issue with progressive bone marrow fibrosis. We revealed that fibrocytes, derived from blood cells, played an important role in this process, and proportion of fibrocytes in peripheral blood and serum IL-1ra level (inhibitor for IL-1 receptor) had a predictive value for bone marrow fibrosis. We also showed that fibrocytes secreted CHI3L1, which stimulated myofibroblasts to produce collagen in bone marrow.

Academic Significance and Societal Importance of the Research Achievements

血球の増加を特徴とする骨髄増殖性腫瘍は、骨髄の線維化の進行によって致命的になりうる難治性の血液疾患である。本研究では骨髄線維化における線維細胞（fibrocyte）の重要性とその役割をさらに明らかにするとともに、侵襲的な骨髄検査をすることなく、末梢血中の線維細胞の割合やIL-1レセプターアンタゴニストの測定によって骨髄の線維化を予測することが可能であることを明らかにした。さらに、線維細胞がCHI3L1の分泌を介して骨髄線維化を誘導していることから、これらを標的とすることで骨髄線維化を軽減する治療法の開発につながると考えられる。

Research Products

• [Journal Article] Increased SLAMF7high monocytes in myelofibrosis patients harboring JAK2V617F provide a therapeutic target of elotuzumab (2019)
  • Author(s): Maekawa Takaaki, Kato Shoichiro, Kawamura Toshikuni, et al.
  • Journal Title: Blood Volume: 134 Issue: 10 Pages: 814-825
  • DOI: 10.1182/blood.2019000051
  • Peer Reviewed
• [Presentation] The frequency of CD34+ cells per CD45+ cells in peripheral blood enumerated by automated method is effective as a non-invasive marker of myelofibrosis in the patients with myeloproliferative neoplasms. (2021)
  • Author(s): Takaaki Maekawa, Hiraku Ogata, Toshikuni Kawamura, Shoichiro Kato, Yukiko Osawa, Ayako Kobayashi, Shinichi Kobayashi, Fumihiko Kimura
  • Organizer: 26th congress of EHA.
  • Int'l Joint Research
• [Presentation] Il-1ra level in the serum is strongly correlated with the JAK2V617F Allele burden, myelofibrosis, splenomegaly and slamf7high CD16－ monocytes in the patients with myeloproliferative neoplasms. (2020)
  • Author(s): Takaaki Maekawa, Shoichiro Kato, Hiraku Ogata, Toshikuni Kawamura, Yukiko Osawa, Ayako Kobayashi, Shinichi Kobayashi, Fumihiko Kimura
  • Organizer: 25th congress of EHA.
  • Int'l Joint Research
• [Presentation] IL-1ra in the serum is correlated with the JAK2V617F allele burden, myelofibrosis, splenomegaly. (2020)
  • Author(s): Takaaki Maekawa, Shoichiro Kato, Hiraku Ogata, Toshikuni Kawamura, Yukiko Osawa, Ayako Kobayashi, Shinichi Kobayashi, Fumihiko Kimura
  • Organizer: 第82回日本血液学会学術集会.
• [Presentation] Il-1ra level in the serum is strongly correlated with the JAK2V617F Allele burden, myelofibrosis, splenomegaly and slamf7high CD16－ monocytes in the patients with myeloproliferative neoplasms (2020)
  • Author(s): Takaaki Maekawa, Shoichiro Kato, Hiraku Ogata, Toshikuni Kawamura, Yukiko Osawa, Ayako Kobayashi, Shinichi Kobayashi, Fumihiko Kimura
  • Organizer: 25th congress of EHA
  • Int'l Joint Research
• [Presentation] Increase of SLAMF7high CD16negative monocytes in the peripheral blood of patients with myelofibrosis in correlation with the JAK2V617F mutation. (2019)
  • Author(s): Shoichiro Kato, Takaaki Maekawa, Hiraku Ogata, et al.
  • Organizer: 24th congress of EHA
  • Int'l Joint Research
• [Presentation] SLAMF7high CD16- monocytes increase in myelofibrosis patients in correlation with JAK2V617F mutation (2019)
  • Author(s): Takaaki Maekawa, Shoichiro Kato, Hiraku Ogata, et al.
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Chitinase 3-like 1 produced by fibrocytes promotes myelofibrosis and is a potent therapeutic target (2019)
  • Author(s): Shoichiro Kato, Takaaki Maekawa, Hiraku Ogata, et al.
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] Chitinase 3-like 1 produced by fibrocytes promotes myelofibrosis (2019)
  • Author(s): Shoichiro Kato, Takaaki Maekawa, Hiraku Ogata, et al.
  • Organizer: 61th Annual Meeting of the American Society of Hematology
  • Int'l Joint Research
• [Presentation] SLAMF7high CD16negative Monocytes Increase in Peripheral Blood of Patients with Myelofibrosis in Correlation with JAK2V617F Mutation (2018)
  • Author(s): Takaaki Maekawa, Shoichiro Kato, Yosuke Okada, Noriaki Tachi, Masahiro Teramoto, Toshikuni Kawamura, Yukiko Osawa, Shinichi Kobayashi, Ken Sato, Michihiro Hashimoto, Shinya Suzu, Kensuke Usuki, Soji Morishita, Marito Araki, Norio Komatsu, Fumihiko Kimura
  • Organizer: 60th Annual Meeting of the American Society of Hematology
  • Int'l Joint Research