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

• 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
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• 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 / iPS細胞 / YAP1 / PD-MSC / リプログラミング / エクソソーム / 骨髄リプログラミング / 白血病 / 骨髄異形成症候群

Outline of Research at the Start

白血病・骨髄異形細胞の遺伝子解析の結果、主にエクソームの範囲で遺伝子変異の概要が明らかとされてきた。一方、最近になって、白血病・骨髄異形症候群の発症進展における間質機能異常の重要性がクローズアップされている。最近、骨髄間質液中には高濃度の細胞外小胞が存在し、間質細胞の造血支持機能の異常を惹起することを報告した。しかしながら、骨髄細胞外小胞はマイクロRNAのみならず、多彩な物質を同時に標的細胞に運搬するため、その役割の全貌は未解決である。本研究では骨髄内細胞外小胞の組成から、その分泌細胞を同定するとともに、異常な骨髄細胞外小胞を正常化することで骨髄リプログラミングという新規治療法の確立を目指す。

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.

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。

Research Products

• [Journal Article] Possible clinical outcomes using early enteral nutrition in individuals with allogeneic hematopoietic stem cell transplantation: A single-center retrospective study (2021)
  • Author(s): Satoshi Iyama, Hiroomi Tatsumi, Tsukasa Shiraishi, Shohei Kikuchi, Tsutomu Sato, Hirofumi Ohnishi, Shin-Ichi Yokota, Masayoshi Kobune
  • Journal Title: Nutrition Volume: 83 Pages: 111093-111093
  • DOI: 10.1016/j.nut.2020.111093
  • Peer Reviewed
• [Journal Article] Six-transmembrane epithelial antigen of the prostate 1 accelerates cell proliferation by targeting c-Myc in liver cancer cells (2021)
  • Author(s): Iijima Kazutaka、Nakamura Hajime、Takada Kohichi、Hayasaka Naotaka、Kubo Tomohiro、Umeyama Yui、Iyama Satoshi、Miyanishi Koji、Kobune Masayoshi、Kato Junji
  • Journal Title: Oncology Letters Volume: 22 Issue: 1 Pages: 546-546
  • DOI: 10.3892/ol.2021.12807
  • Peer Reviewed / Open Access
• [Journal Article] Potential drug?drug interactions in the era of integrase strand transfer inhibitors: a cross-sectional single-center study in Japan (2021)
  • Author(s): Kunimoto Yusuke、Matamura Ryosuke、Ikeda Hiroshi、Fujii Satoshi、Kimyo Tomoko、Kitagawa Manabu、Nakata Hiromasa、Kobune Masayoshi、Miyamoto Atsushi、Fukudo Masahide
  • Journal Title: Journal of Pharmaceutical Health Care and Sciences Volume: 7 Issue: 1 Pages: 43-43
  • DOI: 10.1186/s40780-021-00226-7
  • Peer Reviewed
• [Journal Article] MUTYH is associated with hepatocarcinogenesis in a non-alcoholic steatohepatitis mouse model (2021)
  • Author(s): Sakamoto Hiroki、Miyanishi Koji、Tanaka Shingo、Ito Ryo、Hamaguchi Kota、Sakurada Akira、Sato Masanori、Kubo Tomohiro、Osuga Takahiro、Murase Kazuyuki、Takada Kohichi、Nakabeppu Yusaku、Kobune Masayoshi、Kato Junji
  • Journal Title: Scientific Reports Volume: 11 Issue: 1
  • DOI: 10.1038/s41598-021-83138-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combination of psoas muscle mass index and neutrophil/lymphocyte ratio as a prognostic predictor for patients undergoing <scp>nonsurgical</scp> hepatocellular carcinoma therapy (2021)
  • Author(s): Sugama Yusuke、Miyanishi Koji、Osuga Takahiro、Tanaka Shingo、Hamaguchi Kota、Ito Ryo、Sakamoto Hiroki、Kubo Tomohiro、Ohnuma Hiroyuki、Murase Kazuyuki、Takada Kohich、Kobune Masayoshi、Kato Junji
  • Journal Title: JGH Open Volume: 5 Issue: 12 Pages: 1335-1343
  • DOI: 10.1002/jgh3.12676
  • Peer Reviewed
• [Journal Article] Diffuse large B cell lymphoma with HIV infection presented with disseminated thromboembolism during antiretroviral therapy (2020)
  • Author(s): 池田 博、井山 諭、加藤 淳二、小船 雅義、長島 加奈、藤田 千紗、後藤 亜香利、堀口 拓人、菊地 尚平、村瀬 和幸、高田 弘一
  • Journal Title: Rinsho Ketsueki Volume: 61 Issue: 11 Pages: 1595-1599
  • DOI: 10.11406/rinketsu.61.1595
  • NAID: 130007951912
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Acquired amegakaryocytic thrombocytopenic purpura possibly induced by anti-PD-1 antibody (2020)
  • Author(s): Iyama Satoshi、Takada K.、Yoshida M.、Takahashi D.、Kobune M.
  • Journal Title: Annals of Hematology Volume: 99 Issue: 7 Pages: 1669-1670
  • DOI: 10.1007/s00277-020-04053-y
  • Peer Reviewed
• [Journal Article] 骨髄異形成症候群などの骨髄不全症候群における鉄過剰症の治療 (2020)
  • Author(s): 小船 雅義
  • Journal Title: 臨床血液 Volume: 61 Pages: 753-763
  • NAID: 130007884767
  • Peer Reviewed
• [Journal Article] Successful Treatment by Surgery and Lenvatinib of a Patient with Adrenal Metastasis of Papillary Thyroid Cancer (2020)
  • Author(s): Nakamura Hajime、Takada Kohichi、Murase Kazuyuki、Sakamoto Hiroki、Hayasaka Naotaka、Ishikawa Kazuma、Ikeda Yuki、Yoshida Makoto、Iyama Satoshi、Kobayashi Ko、Shindo Tetsuya、Sugita Shintaro、Miyanishi Koji、Kobune Masayoshi、Masumori Naoya、Kato Junji
  • Journal Title: Case Reports in Oncological Medicine Volume: 2020 Pages: 1-4
  • DOI: 10.1155/2020/2107430
  • Peer Reviewed
• [Journal Article] EPO-R+ myelodysplastic cells with ring sideroblasts produce high erythroferrone levels to reduce hepcidin expression in hepatic cells (2019)
  • Author(s): Miura, S. Kobune, M. Horiguchi, H. Kikuchi, S. Iyama, S. Murase, K. Goto, A. Ikeda, H. Takada, K. Miyanishi, K. Kato, J.
  • Journal Title: Blood Cells Mol Dis Volume: 78 Pages: 1-8
  • DOI: 10.1016/j.bcmd.2019.04.014
  • Peer Reviewed
• [Journal Article] miR-7977 inhibits the Hippo-YAP signaling pathway in bone marrow mesenchymal stromal cells (2019)
  • Author(s): Yoshida, M. Horiguchi, H. Kikuchi, S. Iyama, S. Ikeda, H. Goto, A. Kawano, Y. Murase, K. Takada, K. Miyanishi, K. Kato, J. Kobune, M.
  • Journal Title: PLoS One Volume: 14 Issue: 3 Pages: e0213220-e0213220
  • DOI: 10.1371/journal.pone.0213220
  • Peer Reviewed / Open Access
• [Presentation] CD34+ Positive Myelodysplastic Cells with Ring Sideroblasts or SF3B1 Mutation Produce High Erythroferrone and GDF15 (2020)
  • Author(s): Horiguchi H, Kobune M, Ono K, Shimoyama S, Fujita C, Goto A, Ikeda H, and Iyama S.
  • Organizer: American Society of Hematology
  • Int'l Joint Research
• [Presentation] シンポジウム18「がん診療と輸血医療」:総論 がん診療と貧血． (2020)
  • Author(s): 小船雅義，堀口拓人.
  • Organizer: 第68回日本輸血・細胞治療学会学術総会
• [Presentation] シンポジウム4「輸血医療と鉄代謝」: 輸血後鉄過剰症が引き起こす細胞・臓器障害. (2020)
  • Author(s): 堀口拓人，小船雅義.
  • Organizer: 第68回日本輸血・細胞治療学会学術総会
• [Presentation] Treatment of iron overload in myelodysplastic syndromes and other bone marrow failure diseases. (2019)
  • Author(s): 小船雅義
  • Organizer: 第81回日本血液学会学術集会.