Molecular Abnormalities Caused by Mutations in Epigenetic Regulators of Leukemia

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K16320
• 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: Kyoto University
• Principal Investigator: Ochi Yotaro 京都大学, 医学研究科, 助教 (40883707)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: 急性骨髄性白血病 / エピジェネティクス

Outline of Final Research Achievements

Acute myeloid leukemia (AML) is a refractory hematopoietic neoplasm, and although highly invasive chemotherapy is often used as standard treatment, the development of more tumor-specific stratified therapy is desirable.
In this study, we investigated the potential efficacy of molecularly targeted drugs targeting the transcription system against mutations in epigenetic regulators of AML, particularly cohesin complex components. We established and cultured leukemia cell lines in which cohesin and coexisting mutations were introduced by genome editing, and showed the efficacy of the drugs including the CDK inhibitor. The drug also showed mutation-specific efficacy in a mouse model of leukemia. These findings pave a way toward the development of stratified therapies targeting mutation-specific transcriptional abnormalities.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

白血病は患者間で極めて異なる臨床的・遺伝学的特徴を有するが、大部分の症例では画一的な化学療法や造血幹細胞移植が行われている。本研究ではエピジェネティクス制御因子の変異をもつ白血病細胞で特に転写異常が強く生じ得る点に注目し、変異陽性白血病が転写を阻害する薬剤に脆弱性を示すという仮説について検証を行った。遺伝子変異を導入した白血病細胞株を樹立し、培養実験およびマウスモデルにて転写を阻害するCDK阻害剤の薬効を測定したところ、変異陽性細胞は高い感受性を示した。以上より、白血病に高頻度に認められるエピジェネティクス遺伝子変異を標的とする層別化治療の開発が期待できるものと考えられた。