2021 Fiscal Year Final Research Report

Analysis of the development and pathogenesis of AML/MDS via extracellular vesicles

Research Project

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Project/Area Number	19K08871
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	Sapporo Medical University
Principal Investigator	Kobune Masayoshi 札幌医科大学, 医学部, 教授 (90336389)
Co-Investigator(Kenkyū-buntansha)	井山諭札幌医科大学, 医学部, 講師 (50398319) 池田博札幌医科大学, 医学部, 助教 (60570132) 後藤亜香利札幌医科大学, 医学部, 助教 (60722387) 菊地尚平札幌医科大学, 医学部, 助教 (80515792)
Project Period (FY)	2019-04-01 – 2022-03-31
Keywords	細胞外小胞 / 骨髄間葉系幹細胞 / マイクロRNA / miR-7977 / HIPPO / STK4 / PCBP1 / 急性骨髄性白血病
Outline of Final Research Achievements	The analysis of exome in MDS and AML has revealed the multiple mutations involved in the pathogenesis of these disorders. On the other hand, it has been increasingly focused on the dysfunction of BM microenvironment in the MDS/AML. However, little is known how the dysfunction of BM microenvironment was induced. In this study, high level of miR-7977, miR-8073, and miR-4286 were identified in extracellular vesicles from AML cells. In particular, miR-7977 effect on BM MSCs to reduce the expression of PCBP1 and STK4, resulting in the reduction of multiple mRNA and Hippo signaling, suggesting that it could be involved in the alteration of BM microenvironment favorable to leukemia cell survival. In addition, the possibility of rejuvenation by extracellular vesicles derived from immature cells was investigated. Although the expression of β galactosidase was slightly decreased, no changes of other aging markers were detected. Other strategy may be required for rejuvenation of aging MSCs.
Free Research Field	血液学
Academic Significance and Societal Importance of the Research Achievements	本研究により、MDSやAMLで見られる間質機能異常を誘導する機序の一つとして、白血病細胞から放出される細胞外小胞が関与する可能性が明らかとなった。また、骨髄細胞外小胞を骨髄微細環境の一部と捉えている点も独創的な研究である。この研究成果から白血病由来の細胞外小胞の内容物を用いた分子診断や治療標的とする研究に発展する可能性があり学術的意義が高い。この成果は他の血液腫瘍疾患の他、他の臓器の固形癌にも応用できる研究成果であり、幅広い社会的意義がある。また、細胞外小胞を用いることで老化間葉系幹細胞の一部の老化マーカーを解除できたことは、若返り研究の一つの戦略法として意義がある成果と考えられる。