| Project/Area Number |
17K09000
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Laboratory medicine
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| Research Institution | Kawasaki Medical School |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | MDS / DNMTIs / 白血病 / DNAメチル化 / コレステロール-25-ハイドロキシラーゼ / 25-オキシステロール / CH25H / 25-OHC / ２５－OHC / 臨床検査医学 |
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| Outline of Final Research Achievements |
DNA methyltransferase inhibitors (DNMT inhibitors) are administered for high-risk MDS, but their action mechanisms are not fully understood. We performed a genome-wide DNA methylation assay and focused on cholesterol 25-hydroxylase (CH25H) among the genes whose expression was up-regulated and whose promoter region was hypomethylated after decitabine (DAC) treatment. CH25H produces 25-hydroxycholesterol(25-OHC). Although CH25H mRNA expression level was low in MDS/leukemia cell lines, exposure to DNMT inhibitors enhanced CH25H mRNA expression. The promoter region of CH25H was hypermethylated in HL-60 and MDS-L cells, but DAC induced their hypomethylation together with increased CH25H mRNA expression, activation of CH25H-oxysterol pathway, 25-OHC production and apoptotic cell death.The present study raises a possibility that DNMT inhibitors activate CH25H-oxysterol pathway by their hypomethylating mechanism and induce leukemic cell death.
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| Academic Significance and Societal Importance of the Research Achievements |
骨髄異形成症候群（MDS)は予後良好の血液悪性腫瘍である。治癒は造血幹細胞移植しかないが, 高齢発症が多いため, 移植適応外患者の治療薬について以前から切望されてきた。最近, MDSに対するDNAメチル化阻害薬（DNMTIs）の有用性が指摘されているが, 作用機序の詳細, ターゲットになる遺伝子は同定されていない。今回, 我々は網羅的遺伝子発現解析と次世代シーケンサーによる網羅的メチル化解析を行い, コレステロール-25-ハイドロキシラーゼ（CH25H)の発現増加に注目した。
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