MPN research focusing on ER stress response and tumor-derived fibrocytes

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03713
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: University of Miyazaki
• Principal Investigator: Shimoda Kazuya 宮崎大学, 医学部, 教授 (90311844)
• Co-Investigator(Kenkyū-buntansha): 久冨木 庸子 宮崎大学, 医学部, 講師 (00284836) ; 幣 光太郎 宮崎大学, 医学部, 助教 (20468028) ; 亀田 拓郎 宮崎大学, 医学部, 助教 (30468029)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 骨髄増殖性腫瘍 / 小胞体ストレス / 骨髄線維症

Outline of Final Research Achievements

The cell proliferation mechanism of myeloproliferative neoplasms (MPN) is JAK-STAT signaling activation by JAK2 and CALR mutations. On the other hand, the characteristics of CALR-mutant hematopoietic stem cells (HSCs) and the mechanism of bone marrow fibrosis are unknown, and the mechanisms of bone marrow fibrosis remain to be elucidated.
Using the MPN mouse model, we revealed the gene expression profile of the ER stress pathway in CALR-mutant HSCs. We also clarified the effects of ER stress reduction by chemical chaperones on MPN pathology.We identified the surface antigens of neoplastic fibrocytes, the cells responsible for fibrosis, and their progenitor cells, the neoplastic monocytes. Compounds that inhibit the differentiation of monocytes to fibrocytes were identified using existing and novel compound libraries.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

本研究により明らかになったCALR欠損により生じるERストレス応答亢進とその制御に関する知見、そして骨髄線維化の責任細胞である単球由来の腫瘍性fibrocyteの同定と分化経路、治療標的化に関する知見は、MPNの病態、骨髄線維症の発症機構の解明に大きく貢献するものである。これらの成果は2次性骨髄線維症早期診断法や、現在の標準薬物療法であるJAK阻害剤では改善が乏しい骨髄線維化の新規治療法開発の端緒となることが期待できる。