DNA demethylation therapy in ATL

2018 Fiscal Year Final Research Report

• Project/Area Number: 17H06956
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Tumor therapeutics
• Research Institution: Saga University
• Principal Investigator: Watanabe Tatsuro 佐賀大学, 医学部, 寄附講座准教授 (20595714)
• Research Collaborator: KIMURA shinya ; SUEOKA eisaburo
• Project Period (FY): 2017-08-25 – 2019-03-31
• Keywords: ATL / DNAメチル化 / がん予防 / 診断 / 分子標的薬

Outline of Final Research Achievements

Adult T-cell leukaemia-lymphoma (ATL) is an aggressive haematological malignancy of CD4+ T-cells transformed by human T-cell lymphotropic virus-1 (HTLV-1). We have identified common differentially hypermethylated positions (hyper methylated DMPs) specific to HTLV-1-infected T-cells by comprehensive DNA methylation analysis. Since accumulation of DNA methylation at these sites correlated with ATL development and progression, we investigated the efficacy of DNA demethylating agents. Treatment with decitabine (DAC) inhibited cell growth accompanied by global DNA hypomethylation in HTLV-1-infected cell lines. We found 22 genes, including THEMIS and LAIR1 as negative regulators of TCR signaling, and FHIT as a tumor suppressor, whose expression was down-regulated concomitant with promoter hypermethylation and rescued by DAC treatment. Our results demonstrate that DNA demethylation therapy is a new and effective approach to prevent disease development and progression in ATL.

Free Research Field

造血器腫瘍のエピジェネティクス

Academic Significance and Societal Importance of the Research Achievements

DNAのメチル化異常がHTLV-1感染細胞の増殖や生存に機能的に寄与していることが示され、DNAのメチル化異常を標的にしたATLの新規治療法、予防法の開発の可能性が見いだされた。今回同定したいくつかの遺伝子のメチル化異常をさらに多検体で検証することで、HTLV-1感染者の中でATLを発症する5%の感染者を早期に抽出する新しい指標に応用し、患者毎の発症リスクに応じた経過観察スケジュールの作成にやDNA脱メチル化剤の適応患者の選別に役立つと考える。