Mutual role of a driver mutation and abnormality of histone modification in progression of myeloproliferative neoplasms

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K08365
• 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: Fukushima Medical University
• Principal Investigator: Ikeda Kazuhiko 福島県立医科大学, 医学部, 教授 (90381392)
• 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)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 骨髄増殖性腫瘍 / 病態進展 / 血管病変 / 髄外造血

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.

Free Research Field

骨髄系腫瘍

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。