Development of an agent promoting IKAROS protein destabilization in Multiple myeloma cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07351
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Tohoku University
• Principal Investigator: Ochiai Kyoko 東北大学, 医学系研究科, 助教 (10455785)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 多発性骨髄腫 / 転写因子IKAROS / クロマチン制御因子PC4 / 転写因子IRF4

Outline of Final Research Achievements

Transcription factor (TF) IKAROS is one of effective target molecules in the treatment of Multiple myeloma (MM), and Lenalidomide, an anticancer agent, promotes IKAROS protein degradation via the ubiquitin-proteasome pathway. However, Lenalidomide treatment reduces IKAROS in not only MM cells but also normal lymphoid progenitors, resulted in infectious diseases caused by the reduced number of lymphoid cells. To improve the issue, we focused on our finding that a non-histone chromatin protein PC4 stabilizes IKAROS by the ubiquitin-proteasome pathway independent manner. We found that the expression of PC4 is induced by TF IRF4, which contributes to MM cell proliferation. Importantly, the IRF4-mediated induction of PC4 involves IRF4 accumulation. Therefore, the IRF4-PC4 axis could be an additional effective target for reducing IKAROS protein in MM cells.

Free Research Field

B細胞分化制御

Academic Significance and Societal Importance of the Research Achievements

多発性骨髄腫は抗体を産生する形質細胞が異常増殖する血液細胞の癌で、抗がん剤による化学療法が治療選択に挙げられる。一方、抗がん剤の腫瘍治療有効濃度は感染症など重篤な副作用を伴うため、作用機序の異なる抗がん剤を組み合わせて各薬剤の副作用を最小限に留めることが望ましい。転写因子IKAROSは多発性骨髄腫の治療標的分子として有効で、本研究で既存の薬剤標的であるIKAROSタンパク質分解誘導の分子機構とは異なる分子機構を見いだすことで、IKAROS機能阻害を目的とした新たな薬剤の開発に繋がる。そして、既存の薬剤との組み合わせにより効果的かつ副作用を減らした治療戦略に発展することが期待できる。