2020 Fiscal Year Final Research Report
Enhanced ER stress response in MPN cells involved in development of myelofibrosis through secretion of GRP78
| Project/Area Number |
18K08319
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | University of Yamanashi |
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Principal Investigator |
KIRITO Keita 山梨大学, 大学院総合研究部, 教授 (90306150)
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| 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)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Keywords | 小胞体ストレス / 骨髄線維症 / ATF4 / MMP9 / GRP78 / Lysyl oxidase |
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| 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.
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| Free Research Field |
血液内科学
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| 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。
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