Targeting aberrant DNA hypermethylation as a driver of ATL leukemogenesis by using the new oral demethylating agent OR-2100

DOI PDF PubMed 被引用文献14件 参考文献51件
  • Tatsuro Watanabe
    Department of Drug Discovery and Biomedical Sciences, Faculty of Medicine, Saga University, Saga, Japan;
  • Satoshi Yamashita
    Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan;
  • Hiroshi Ureshino
    Department of Drug Discovery and Biomedical Sciences, Faculty of Medicine, Saga University, Saga, Japan;
  • Kazuharu Kamachi
    Department of Drug Discovery and Biomedical Sciences, Faculty of Medicine, Saga University, Saga, Japan;
  • Yuki Kurahashi
    Department of Drug Discovery and Biomedical Sciences, Faculty of Medicine, Saga University, Saga, Japan;
  • Yuki Fukuda-Kurahashi
    Department of Drug Discovery and Biomedical Sciences, Faculty of Medicine, Saga University, Saga, Japan;
  • Nao Yoshida
    Department of Drug Discovery and Biomedical Sciences, Faculty of Medicine, Saga University, Saga, Japan;
  • Naoko Hattori
    Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan;
  • Hideaki Nakamura
    Department of Transfusion Medicine,
  • Akemi Sato
    Department of Clinical Laboratory Medicine, Faculty of Medicine, and
  • Atsushi Kawaguchi
    Section of Clinical Cooperation System, Center for Comprehensive Community Medicine, Faculty of Medicine, Saga University, Saga, Japan; and
  • Naoko Sueoka-Aragane
    Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan;
  • Kensuke Kojima
    Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan;
  • Seiji Okada
    Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
  • Toshikazu Ushijima
    Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan;
  • Shinya Kimura
    Department of Drug Discovery and Biomedical Sciences, Faculty of Medicine, Saga University, Saga, Japan;
  • Eisaburo Sueoka
    Department of Clinical Laboratory Medicine, Faculty of Medicine, and

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<jats:title>Abstract</jats:title> <jats:p>Adult T-cell leukemia-lymphoma (ATL) is an aggressive hematological malignancy of CD4+ T cells transformed by human T-cell lymphotropic virus-1 (HTLV-1). Most HTLV-1–infected individuals are asymptomatic, and only 3% to 5% of carriers develop ATL. Here, we describe the contribution of aberrant DNA methylation to ATL leukemogenesis. HTLV-1–infected T-cells and their uninfected counterparts were separately isolated based on CADM1 and CD7 expression status, and differentially methylated positions (DMPs) specific to HTLV–infected T cells were identified through genome-wide DNA methylation profiling. Accumulation of DNA methylation at hypermethylated DMPs correlated strongly with ATL development and progression. In addition, we identified 22 genes downregulated because of promoter hypermethylation in HTLV-1–infected T cells, including THEMIS, LAIR1, and RNF130, which negatively regulate T-cell receptor (TCR) signaling. Phosphorylation of ZAP-70, a transducer of TCR signaling, was dysregulated in HTLV-1–infected cell lines but was normalized by reexpression of THEMIS. Therefore, we hypothesized that DNA hypermethylation contributes to growth advantages in HTLV-1–infected cells during ATL leukemogenesis. To test this idea, we investigated the anti-ATL activities of OR-1200 and OR-2100 (OR21), novel decitabine (DAC) prodrugs with enhanced oral bioavailability. Both DAC and OR21 inhibited cell growth, accompanied by global DNA hypomethylation, in xenograft tumors established by implantation of HTLV-1–infected cells. OR21 was less hematotoxic than DAC, whereas tumor growth inhibition was almost identical between the 2 compounds, making it suitable for long-term treatment of ATL patient-derived xenograft mice. Our results demonstrate that regional DNA hypermethylation is functionally important for ATL leukemogenesis and an effective therapeutic target.</jats:p>

収録刊行物

  • Blood

    Blood 136 (7), 871-884, 2020-08-13

    American Society of Hematology

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