Elucidating the mechanisms of clonal evolution of myeloid neoplasms with germline predisposition

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08394
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Kyoto University
• Principal Investigator: Kon Ayana 京都大学, 医学研究科, 特定講師 (20772403)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 骨髄異形成症候群 / 急性骨髄性白血病 / 胚細胞変異

Outline of Final Research Achievements

In this study, we investigated the molecular mechanisms underlying the clonal selection of hematopoietic cells harboring DDX41 germline/somatic mutations, which were previously identified through genetic analysis of late-onset familial and sporadic myeloid neoplasms. We generated Ddx41 mutant mouse models and examined the molecular pathogenesis using methodology including single-cell and omics analysis. Through this, we have elucidated the cell-autonomous/non-autonomous molecular pathogenesis induced by the Ddx41 mutations. Furthermore, we investigated the potential for identifying new therapeutic targets based on our discoveries.

Free Research Field

血液腫瘍病態学、腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では、先天性骨髄系腫瘍の最大のリスク因子であるDDX41胚細胞/体細胞変異に関して、変異をもつ細胞がクローン選択を受ける分子メカニズムの詳細な検討により、変異により惹起される細胞自律的/非自律的な分子病態を多角的に解明した点で、高い学術的な独自性を有する。さらに、新規治療標的の開発の可能性も検討し、がんの治療予後の向上に資する社会的意義の高い研究成果が得られた。本研究で新たに生じた疑問に関する検討を継続し、病態のさらなる理解とその制御による新たな治療法の開発を目指したい。