Mutual role of a driver mutation and abnormality of histone modification in progression of myeloproliferative neoplasms
| Project/Area Number |
18K08365
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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 | Fukushima Medical University |
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Principal Investigator |
Ikeda Kazuhiko 福島県立医科大学, 医学部, 教授 (90381392)
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| Co-Investigator(Kenkyū-buntansha) |
大河原 浩 福島県立医科大学, 医学部, 准教授 (10381360)
橋本 優子 福島県立医科大学, 医学部, 教授 (60305357)
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | 骨髄増殖性腫瘍 / 病態進展 / 血管病変 / 髄外造血 / CALR / CALR変異 / ポリコーム抑制複合体 / カルレチクリン / ドライバー変異 / ヒストン修飾 / HMGA2 |
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| Outline of Final Research Achievements |
In this study, we aimed to clarify roles of the histone modifiers in the pathogenesis of myeloproliferative neoplasm (MPN) progression. We generated knock-in mice carrying frameshifted Calr (Calr-del10) using genome edition, which showed MPN-like hematopoiesis. Bone marrow transplant recipients from Calr-del10 mice showed impaired reconstitution of Calr-mutated hematopoietic stem cells associated with reduced expression of polycomb recessive complex 2-related genes, whereas Calr-del10 macrophages with JAK-STAT activation accumulated in the perivascular region of lungs and contributed to pulmonary arterial remodeling. In addition, we established the mouse models with vascular remodeling due to the hematopoietic JAK2 mutation, which also showed extramedullary hematopoiesis in lungs. In these models, abnormalities in histone modifiers may lead to MPN progression.
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| Academic Significance and Societal Importance of the Research Achievements |
我々はゲノム編集法を行い、Calr変異についてMPN造血、血管病変および髄外造血を検討しうる動物モデルを確立した。Jak2変異についても、マウスモデルに低酸素曝露を行うことにより、肺血管のリモデリングを促進するモデルを確立した。これらによって髄外造血と血管病変がつながる可能性が明らかになり、病態解明の一助となった。ヒストン修飾因子の異常がMPN幹細胞の機能を増強させるデータを得ており、病態進展を検討する上でも有用なツールとなると考えている。
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Report
(5 results)
Research Products
(42 results)
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[Journal Article] Crucial role of hematopoietic JAK2V617F in the development of aortic aneurysms.2021
Author(s)
Yokokawa T, Misaka T, Kimishima Y, Wada K, Minakawa K, Sugimito K, Ishida T, Morishita S, Komatsu N, Ikeda K, Takeishi Y.
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Journal Title
Haematologica
Volume: -
Issue: 7
Pages: 1910-1922
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Myeloproliferative neoplasm-driving Calr frameshift promotes the development of pulmonary hypertension in mice.2021
Author(s)
Minakawa K, Yokokawa T, Ueda K, Nakajima O, Misaka T, Kimishima Y, Wada K, Tomita Y, Miura S, Sato Y, Mimura K, Sugimoto K, Nakazato K, Nollet KE, Ogawa K, Ikezoe T, Hashimoto Y, Takeishi Y, Ikeda K.
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Journal Title
J Hematol Oncol.
Volume: 14
Issue: 1
Pages: 52-52
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] 骨髄線維症に対する治療2020
Author(s)
桐戸 敬太、竹中 克斗、池田 和彦
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Journal Title
Rinsho Ketsueki
Volume: 61
Issue: 2
Pages: 166-174
DOI
NAID
ISSN
0485-1439, 1882-0824
Related Report
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[Presentation] Clonal hematopoiesis with JAK2V617F promotes pulmonary hypertension through ALK1.2020
Author(s)
Kimishima Y, Misaka T, Yokokawa T, Wada K, Ueda K, Sugimoto K, Minakawa K, Nakazato K, Ishida T, Oshima M, Koide S, Shide K, Shimoda K, Iwama A, Ikeda K, Takeishi Y.
Organizer
American Heart Association Scientific Session 2020.
Related Report
Int'l Joint Research
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