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Enhanced ER stress response in MPN cells involved in development of myelofibrosis through secretion of GRP78

Research Project

Project/Area Number 18K08319
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionUniversity of Yamanashi

Principal Investigator

KIRITO Keita  山梨大学, 大学院総合研究部, 教授 (90306150)

Co-Investigator(Kenkyū-buntansha) 川島 一郎  山梨大学, 大学院総合研究部, 助教 (20622369)
三森 徹  山梨大学, 大学院総合研究部, 講師 (80377514)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Keywords小胞体ストレス / 骨髄線維症 / ATF4 / MMP9 / GRP78 / Lysyl oxidase / 骨髄間質細胞 / lysyl oxidase / type1 コラーゲン / SAPK/JNK / metformin / ERストレス / MMP / TIMP / UPR / JAK2V617F / 分子シャペロン / メトホルミン
Outline of Final Research Achievements

Initially, we confirmed activation of ER stress response molecules including ATF4, ATF6 and XBP1s in MPN derived cell lines. Enhanced expression of ATF4 were also found in primary megakaryocytes from MPN patients. GRP78, which regulates ER stress response as downstream effector of ATF4, were also elevated in MPN cells and secreted into culture media. Ruxolitinib, a relatively selective inhibitor for JAK kinase, blocked activation of ATF4 and reduced GRP78 secretion from MPN cells. For further study, we cultured MPN cells with human bone marrow derived fibroblast cell line, HS-5. Co-culture with MPN cells enhanced expression of alpha-smooth muscle actin, one of the important marker for cancer associated fibroblast. Expression of lysyl oxidase, an enzyme which mediates cross-linking of collagen fibers, was also increased. Taken together , enhanced ER stress response in MPN cells might contribute to development of myelofibrosis through GRP78-mediated activation of fibroblast.

Academic Significance and Societal Importance of the Research Achievements

MPNに併発する骨髄線維症は、造血不全による貧血進行、炎症性サイトカインの増加による倦怠感などの全身症状の増悪、髄外造血による脾腫の進行など生命予後のみならず生活の質を極めて不良とする。一方、その効果的な治療法は確立されていない。
本研究により、MPN細胞での小胞体ストレス亢進が起点となり、骨髄環境内にGRP78が放出されることが、骨髄線維芽細胞を活性化させ線維化進行につながるとのモデルを提示することができた。この結果より、骨髄線維化進行を抑制する新たな手段として、MPN細胞での小胞体ストレスの抑制、中和抗体などを用いた骨髄微小環境内におけるGRP78の機能抑制などへ発展することが期待される。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (16 results)

All 2020 2019 2018

All Journal Article (6 results) (of which Peer Reviewed: 6 results) Presentation (10 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results)

  • [Journal Article] Expansion of paroxysmal nocturnal hemoglobinuria clones in MPLW515L mutation harboring primary myelofibrosis2020

    • Author(s)
      Kirito Keita
    • Journal Title

      Annals of Hematology

      Volume: 99 Issue: 11 Pages: 2707-2709

    • DOI

      10.1007/s00277-020-04088-1

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Myeloid neoplasm with isolated del(5q) and the MPLW515L mutation fulfills the WHO diagnostic criteria for ET2020

    • Author(s)
      Kirito Keita
    • Journal Title

      International Journal of Hematology

      Volume: 112 Issue: 2 Pages: 238-242

    • DOI

      10.1007/s12185-020-02872-3

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study2020

    • Author(s)
      Kiladjian Jean-Jacques et al.
    • Journal Title

      The Lancet Haematology

      Volume: 7 Issue: 3 Pages: e226-e237

    • DOI

      10.1016/s2352-3026(19)30207-8

    • Related Report
      2020 Annual Research Report 2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Bone Marrow Invasion of Small Cell Neuroendocrine Carcinoma of the Endometrium: A Diagnostic Pitfall Mimicking a Haematological Malignancy2019

    • Author(s)
      Kawashima Ichiro、Fukasawa Hiroko、Kasai Kazunari、Kumagai Takuma、Koshiishi Megumi、Nakajima Kei、Kondo Tetsuo、Hashi Akihiko、Hirata Shuji、Kirito Keita
    • Journal Title

      Internal Medicine

      Volume: 58 Issue: 17 Pages: 2561-2568

    • DOI

      10.2169/internalmedicine.2533-18

    • NAID

      130007700192

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2019-09-01
    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Glycolytic enzyme hexokinase II is a putative therapeutic target in B-cell malignant lymphoma2019

    • Author(s)
      Nakajima Kei、Kawashima Ichiro、Koshiisi Megumi、Kumagai Takuma、Suzuki Megumi、Suzuki Jun、Mitsumori Toru、Kirito Keita
    • Journal Title

      Experimental Hematology

      Volume: 78 Pages: 46-55.e3

    • DOI

      10.1016/j.exphem.2019.09.023

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Molecular response of CSF3R T618I harboring chronic neutrophilic leukemia after induction chemotherapy linked to cord blood transplantation2019

    • Author(s)
      Kawashima Ichiro、Kumagai Takuma、Suzuki Megumi、Suzuki Jun、Koshiishi Megumi、Nakajima Kei、Kirito Keita
    • Journal Title

      Annals of Hematology

      Volume: 98 Issue: 9 Pages: 2249-2250

    • DOI

      10.1007/s00277-019-03733-8

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] Aberrant regulation of extracellular matrix homeostasis by JAK2V617F2020

    • Author(s)
      Kei Nakajima, Keita Kirito
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Possible link between the development of myelofibrosis and autoimmune action in AITL2020

    • Author(s)
      Minori Matsuura et al.
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 8p11骨髄増殖症候群と類縁疾患2019

    • Author(s)
      桐戸敬太
    • Organizer
      第81回日本血液学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 骨髄線維症に対する治療 造血幹細胞移植か?薬物療法か?2019

    • Author(s)
      桐戸敬太、竹中克斗、池田和彦
    • Organizer
      第81回日本血液学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] APL細胞の細胞表面マーカーの特徴と限界2019

    • Author(s)
      細川 恵理子, 輿石 めぐみ, 鈴木 潤, 熊谷 拓磨, 鈴木 愛, 川島 一郎, 中島 圭, 桐戸 敬太
    • Organizer
      第81回日本血液学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 日本における二次性骨髄線維症の予後予測モデルの比較検討2019

    • Author(s)
      鈴木愛、鈴木潤、輿石めぐみ、川島一郎、中嶌圭、三森徹、桐戸敬太
    • Organizer
      第81回日本血液学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] 骨髄増殖腫瘍における18F-FDG-PET/CT所見2019

    • Author(s)
      鈴木潤、佐藤葉子、輿石めぐみ、鈴木愛、川島一郎、中嶌圭、桐戸敬太
    • Organizer
      第81回日本血液学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] CSF3RT618I変異検出により診断することができた慢性好中球性白血病2019

    • Author(s)
      川島一郎、鈴木潤、熊谷琢磨、鈴木愛、輿石めぐみ、中嶌圭、桐戸敬太
    • Organizer
      第81回日本血液学会学術集会
    • Related Report
      2019 Research-status Report
  • [Presentation] Metformin suppresses expression of pre-fibrotic Enzyme Lysyl-oxidase levels through Inhibition of UPR in MPN cells2018

    • Author(s)
      Megumi Suzuki, Jun Shuzuki, Megumi Koshiishi, Ichiro kawashima, Kei Nakajima, Keita Kirito
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Metformin suppresses expression of pre-fibrotic Enzyme Lysyl-oxidase levels through Inhibition of UPR in MPN cells2018

    • Author(s)
      Megumi Suzuki, Jun Shuzuki, Megumi Koshiishi, Ichiro kawashima, Kei Nakajima, Keita Kirito
    • Organizer
      第60回米国血液学会
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2022-01-27  

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