Myeloid leukemogenes via R-loop accumulation caused by RNA helicase mutations

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08419
• 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: National Cancer Center Japan (2023); Kumamoto University (2021-2022)
• Principal Investigator: Matsui Hirotaka 国立研究開発法人国立がん研究センター, 中央病院, 科長 (60379849)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: RNAヘリケース / R-loop / RNAスプライシング / 骨髄異形成症候群 / 急性骨髄性白血病 / DDX41

Outline of Final Research Achievements

It has been revealed that the development of myeloid neoplasms, including acute myeloid leukemia and myelodysplastic neoplasms, is associated with genetic background to a certain degree, in which the DDX41 gene variant is most frequently observed in such neoplasms.
This study showed that DDX41 plays a role in coordinating transcription and DNA replication, both of which are fundamental in cellular regulation. A defect in DDX41 function or decreased expression causes DNA replication stress. However, since the stress is mild enough for cells to overlook during S phase, cells enter mitosis without complete resolution of the replication stress. As a result, DNA instability is increased in the postmitotic cells, which ultimately leads to the transformation of hematopoietic cells.

Free Research Field

血液腫瘍学

Academic Significance and Societal Importance of the Research Achievements

固形腫瘍と同じく、血液腫瘍においても遺伝子パネル検査が医療実装され、検査結果が治療方針の決定や予後予測、疾患分類などに用いられようとしている。一方で、血液腫瘍の治療法をさらに充実させるうえで、遺伝子の異常が疾患を発症させる機序を理解することが重要である。
本研究では、遺伝的背景を伴う血液腫瘍に特に関与するDDX41に焦点を当て、DDX41の発現量の低下や機能障害がどのように血液細胞を変化させるか解析した。その結果、DDX41がDNAの複製と転写とを連携させる機能を有し、DDX41の機能障害が細胞分裂を起こしたあとの細胞にDNA不安定性をもたらすことを明らかにし、疾患の発症機序解明に寄与した。