Roles of ribosome biogenesis disorder in the development of hematopoietic malignancies

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08334
• 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: Kumamoto University
• Principal Investigator: MATSUI HIROTAKA 熊本大学, 大学院生命科学研究部(医), 教授 (60379849)
• Co-Investigator(Kenkyū-buntansha): 神力 悟 熊本大学, 大学院生命科学研究部(医), 准教授 (00583048)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: RNAヘリケース / 骨髄異形成症候群 / 急性骨髄性白血病

Outline of Final Research Achievements

In this study, we analyzed the molecular function of DDX41, a DEAD-box type RNA helicase, to elucidate molecular pathogenesis of myeloid malignancies. We performed a comprehensive translation analysis by taking advantage of ribosome-profiling method and found that transcription and translation are only marginally correlate with each other. We also found that ribosome-associated proteins were selectively induced at translation level when the expression of DDX41 was decreased. This is possibly due to the presence of a feedback regulation against the disorder of ribosome biogenesis by DDX41 inhibition/dysfunction, and we assume this newly identified regulation system would be involved in the hematopoiesis and/or leukemogenesis. The results have been compiled into a manuscript and is currently being submitted to a scientific journal.

Free Research Field

血液腫瘍学

Academic Significance and Societal Importance of the Research Achievements

造血器腫瘍の一定の割合で、DDX41遺伝子の変異を有する例が見出される。DDX41はRNAヘリケースと呼ばれる酵素をコードする遺伝子のひとつであるが、DDX41の造血細胞における役割は不明であり、本遺伝子の変異が造血器腫瘍を起こす機序も未解明であった。
我々はこれまでにDDX41がリボソームRNAのプロセシングを介してリボソーム生合成に関与することを示してきたが、今回さらに本研究を発展させ、網羅的な翻訳解析を行うことで、本分子の翻訳制御機構への関わりを検討した。DDX41の発現を抑制した細胞ではリボソーム生合成関連分子の発現が翻訳レベルで増加することを明らかにし、腫瘍発症への関与を示した。