title: Hypomethylation of the Treg-Specific Demethylated Region in FOXP3 Is a Hallmark of the Regulatory T-cell Subtype in Adult T-cell Leukemia.
abstract: Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1. Because of its immunosuppressive property and resistance to treatment, patients with ATL have poor prognoses. ATL cells possess the regulatory T cell (Treg) phenotype, such as CD4 and CD25, and usually express forkhead box P3 (FOXP3). However, the mechanisms of FOXP3 expression and its association with Treg-like characteristics in ATL remain unclear. Selective demethylation of the Treg-specific demethylated region (TSDR) in the FOXP3 gene leads to stable FOXP3 expression and defines natural Tregs. Here, we focus on the functional and clinical relationship between the epigenetic pattern of the TSDR and ATL. Analysis of DNA methylation in specimens from 26 patients with ATL showed that 15 patients (58%) hypomethylated the TSDR. The FOXP3(+) cells were mainly observed in the TSDR-hypomethylated cases. The TSDR-hypomethylated ATL cells exerted more suppressive function than the TSDR-methylated ATL cells. Thus, the epigenetic analysis of the FOXP3 gene identified a distinct subtype with Treg properties in heterogeneous ATL. Furthermore, we observed that the hypomethylation of TSDR was associated with poor outcomes in ATL. These results suggest that the DNA methylation status of the TSDR is an important hallmark to define this heterogeneous disease and to predict ATL patient prognosis.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Shimazu
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimazu
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. hishiza@kuhp.kyoto-u.ac.jp.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Hishizawa
authors.affiliation: Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Hamaguchi
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Sugino
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Sumie
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kawahara
authors.affiliation: Department of Internal Medicine, Division of Hematology, Rheumatology and Respiratory Medicine, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Japan.
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Kadowaki
authors.affiliation: Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Kashima, Japan.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Nishikawa
authors.affiliation: Department of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Japan.
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Takaori-Kondo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D015415:Biomarkers; D060908:CTLA-4 Antigen / Q000235:genetics; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D016356:Gene Products, tax / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D056747:Immunomodulation; D016130:Immunophenotyping; D053208:Kaplan-Meier Estimate; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000954:Antigens, Surface; D015415:Biomarkers; D060908:CTLA-4 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016356:Gene Products, tax; C111431:IKZF2 protein, human; C514970:tax protein, Human T-lymphotrophic virus 1; D051740:Ikaros Transcription Factor