Investigation of a causal gene of familial myelodysplastic syndromes and its molecular mechanism

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K16181
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: TAKAOKA KENSUKE 東京大学, 医学部附属病院, 助教 (60793180)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 家族性骨髄異形成症候群

Outline of Final Research Achievements

Previous our research revealed that HLTF E259K is one of the candidate gene mutations of familial MDS. Molecularly, we found that an E259K mutation reduced the binding capacity of HLTF with MMS2. In murine bone marrow transplantation experiments, we revealed that the peripheral blood chimerism of the recipients with Hltf knockdown cells tended to be greater than that of control mice. We also found that the bone marrow c-kit positivity was also increased in Hltf shRNA-transduced cells compared with control-transduced cells in the bone marrow transplantation assay. To evaluate whether the HLTF mutation actually contributes to a DNA double-strand break repair deficiency, we performed mutation signature analysis of somatic mutations in samples of both MDS patients. BRCA mutational signature was detected in both familial MDS patients, suggesting that a DNA double-strand break repair was impaired in the HLTF-mutated familial MDS somatic samples.

Free Research Field

血液・腫瘍学

Academic Significance and Societal Importance of the Research Achievements

先行研究と併せ、家族性骨髄異形成症候群（MDS）の家系を用いて未報告のHLTF E259K 生殖細胞変異を同定し、患者検体においてDNA二本鎖切断修復低下を示唆するBRCA変異シグネチャーを明らかにした。分子機構として、HLTF変異体とMMS2との複合体形成能が低下し、（先行研究と併せ）PCNAポリユビキチン化が障害されていることを示した。稀少疾患であり分子機構も未知の部分が多い家族性MDSの検体を用いて全エクソンシーケンスを施行し未報告の生殖細胞変異を同定、さらには機能解析まで施行した本研究の意義は大きいと考えられる。今後HLTFと血液腫瘍のさらなる解析が望まれる。