Development of a new myeloma therapy targeting DOT1L

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K17836
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Sapporo Medical University
• Principal Investigator: Ishiguro Kazuya 札幌医科大学, 医学部, 助教 (90784439)
• Project Period (FY): 2021-11-01 – 2023-03-31
• Keywords: 多発性骨髄腫

Outline of Final Research Achievements

Epigenetic mechanisms such as histone modification play key roles in the pathogenesis of multiple myeloma (MM). We previously showed that DOT1L, a histone H3 lysine 79 (H3K79) methyltransferase is a potential therapeutic target in MM. In this study, we further evaluated the antitumor effect of DOT1L inhibition in MM. CRISPR studies showed that survival of MM was strongly dependent on DOT1L. Transcriptome analysis revealed that DOT1L inhibition upregulated interferon (IFN) signaling in MM cells. Notably, DOT1L inhibition increased expression of endogenous retrovirus (ERV) genes in MM cells. On the other hand, we also found that dual EZH2/G9a inhibition also increased expression of ERV genes and upregulated IFN-stimulated genes in MM cells. A combination of an EZH2 inhibitor and a G9a inhibitor strongly suppressed MM cell proliferation in vitro by inducing cell cycle arrest and apoptosis.
These results suggest that histone modifiers may be an effective therapeutic target for MM.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

DOT1Lは唯一のH3K79メチル化酵素であり、転写活性化に関与することが知られている。DOT1L阻害剤の一つであるEPZ-5676は、MLL関連白血病の第I相試験において一定の奏効率と安全性を示した。一方、多発性骨髄腫(MM)におけるDOT1L阻害剤の効果を明らかにしたのは、我々の研究が世界初である。本研究は今後のMMにおけるDOT1L阻害剤による臨床試験など、MMの新たな治療戦略の開発に寄与するものと考える。