Stratification of patients with MDS for epigenetic agent from the viewpoint of cholesterol metabolic enzyme

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07404
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Kawasaki Medical School
• Principal Investigator: Tsujioka Takayuki 川崎医科大学, 医学部, 准教授 (50330551)
• Project Period (FY): 2021-04-01 – 2024-03-31
• 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

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.

Free Research Field

血液検査学

Academic Significance and Societal Importance of the Research Achievements

骨髄異形成症候群（MDS)は予後不良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が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。そしてCH25Hメチル化の観点から、MDS患者の予後あるいは治療法の層別化を試みた。