Elucidation of the pathogenesis of leukemia with cohesin mutations and development of novel treatment

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22809
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Kyoto University
• Principal Investigator: Ochi Yotaro 京都大学, 医学研究科, 助教 (40883707)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: 白血病 / コヒーシン

Outline of Final Research Achievements

Approximately 10-20% of myeloid neoplasms have mutations in cohesin complex genes, but the molecular mechanisms by which cohesin mutations cause leukemia are not fully understood. This study aims to elucidate the molecular abnormalities caused by cohesin mutations and to develop mutation-specific therapies.
We applied genome editing to establish cohesin-deficient leukemia cell lines. Some anticancer drugs targeting the epigenome showed specific growth inhibitory effects on the cohesin-deficient lines. This effect was also observed in a transplantation model in immunodeficient mice. In addition, a new multiple mutant mouse model of cohesin mutation and other driver gene mutations was generated to demonstrate the cooperative effects of both genes at the phenotypic and molecular levels.

Free Research Field

造血器腫瘍

Academic Significance and Societal Importance of the Research Achievements

本研究では、白血病の約10-20％と高頻度に認められるコヒーシン遺伝子変異の意義を詳細に解析した。ゲノム編集技術によって、白血病のコヒーシン遺伝子変異を細胞株やマウスモデルで再現することで、分子病態の解明や新規治療開発などの実験を可能にした。これらの新規に作成した遺伝子変異モデルを活用することで、コヒーシン変異が白血病を引き起こす機序を明らかにするとともに、コヒーシン遺伝子変異を特異的に標的とする新規の抗癌剤候補を同定することができた。