Understanding of multiple myeloma IMiDs resistance via extracellular vesicles

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K20803
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: National Institute of Health Sciences (2023); Tokyo Medical University (2022)
• Principal Investigator: Yamamoto Tomofumi 国立医薬品食品衛生研究所, 生物薬品部, 任期付研究員 (40963369)
• Project Period (FY): 2022-08-31 – 2024-03-31
• Keywords: 細胞外小胞 / エクソソーム / 多発性骨髄腫 / 薬剤耐性

Outline of Final Research Achievements

In this study, we focused on lenalidomide resistance in multiple myeloma cells. Previously, we showed that lenalidomide resistant cells more secreted EVs than those of parental cells. EV secretion was regulated by the LAMP2 and SORT1 genes in resistant cells. In this study, we attempted to identify the molecular mechanisms how these genes are upregulated in parental cells. As a result, we identified that the expression level of SORT1 was regulated by LAMP2 gene. Also, the expression level of LAMP2 was correlated with the expression of cereblon, which is a target protein of lenalidomide. Finally, we performed small-RNAseq to determine important microRNAs in the resistant cell-derived EVs. Several microRNAs that have been reported to be involved in drug resistance were included.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

多発性骨髄腫は近年、抗体医薬品を含む様々な治療薬が承認され、患者の予後は大きく改善した。しかしながら、薬剤への感受性がなくなり、いずれは再発を来たす、治癒困難な造血器腫瘍である。特に薬剤耐性による使用できる治療薬の減少は患者のQOLに大きく影響することから薬剤耐性機構を理解することは意義があるといえる。骨髄腫は様々なクローンが存在するヘテロな集団であり、さまざまな抵抗性獲得機構が存在すると考えられている。以前EVの分泌を抑制することで耐性獲得済み細胞から感受性株への抵抗性の伝播が抑制できることを報告した。本検討ではなぜ耐性株が生まれるのかに着目しており、骨髄腫治療戦略において重要である。