Overcoming resistance to new drug in hematological malignancy tageting LncRNA.

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07716
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Keio University
• Principal Investigator: ICHIKAWA DAIJU 慶應義塾大学, 薬学部(芝共立), 助教 (60462793)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 多発性骨髄腫 / 免疫調節薬 / CRBN非依存性 / lncRNA

Outline of Final Research Achievements

In this study, we focused on the mechanism of lncRNA to IMiDs resistance in multiple myeloma (MM). We identified 3 lncRNAs (XIST, OVAAL, LINC02397) that are up-regulated in lenalidomide-sensitive MM cell lines using DNA microarray and GSEA. Moreover, MMRF-CoMMpass study indicated that patients with XISTlowOVAALhigh LINC02937low expressions are a significantly shorter overall survival (OS) in comparison to patients with XISThighOVAALlow LINC02937high expressions. GSEA data also showed that the gene set “ZHAN MULTIPLE MYELOMA MS UP” involved in the poor prognosis of multiple myeloma was enriched. We demonstrate that one gene in the enriched gene set contributed to lenalidomide resistance by the results of in vitro assays.

Free Research Field

分子生物学に基づくがん免疫学

Academic Significance and Societal Importance of the Research Achievements

多発性骨髄腫(MM)においてIMiDs やPIs といった薬剤が開発され治療効果が得られているが, これらの治療薬をもってしても治癒に至らず, さらには抵抗性を示す難治性多発性骨髄腫がある. 本研究においてレナリドミドの感受性に起因するlncRNAとしてXIST, LINC02397を同定した. これらlncRNAのさらなる分子機序を解明することで, 臨床現場においてがん患者さんへの薬剤選択に役立つといったプレシジョン・メディシンへの応用に繋がり, 難治性多発性骨髄腫だけでなく予後絶対不良なマントル細胞リンパ腫に対する新規治療薬開発に繋がることが期待される.