Hypomethylation of the Treg-Specific Demethylated Region in FOXP3 Is a Hallmark of the Regulatory T-cell Subtype in Adult T-cell Leukemia
Hypomethylation of the Treg-Specific Demethylated Region in FOXP3 Is a Hallmark of the Regulatory T-cell Subtype in Adult T-cell Leukemia
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DOI：
10.1158/2326-6066.cir-15-0148
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发表时间：
2015-12
影响因子：
10.1
通讯作者：
Yayoi Shimazu;Y. Shimazu;M. Hishizawa;M. Hamaguchi;Y. Nagai;N. Sugino;Sumie Fujii;M. Kawahara;N. Kadowaki;H. Nishikawa;S. Sakaguchi;A. Takaori-Kondo
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文献类型：
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作者：
Yayoi Shimazu;Y. Shimazu;M. Hishizawa;M. Hamaguchi;Y. Nagai;N. Sugino;Sumie Fujii;M. Kawahara;N. Kadowaki;H. Nishikawa;S. Sakaguchi;A. Takaori-Kondo
成人T细胞白血病细胞的亚型可以根据其FOXP 3基因的低甲基化状态来区分。这些细胞具有Treg特性，患者预后不良。成人T细胞白血病（ATL）是由人类T细胞白血病病毒1型引起的侵袭性T细胞恶性肿瘤。由于其免疫抑制特性和对治疗的抗性，ATL患者的预后较差。ATL细胞具有调节性T细胞（Treg）表型，例如CD 4和CD 25，并且通常表达叉头盒P3（FOXP 3）。然而，在ATL中FOXP 3表达的机制及其与Treg样特征的关联仍不清楚。FOXP 3基因中Treg特异性去甲基化区域（TSDR）的选择性去甲基化导致稳定的FOXP 3表达并定义天然TcB。在这里，我们专注于TSDR和ATL的表观遗传模式之间的功能和临床关系。对26例ATL患者标本的DNA甲基化分析显示，15例（58%）患者的TSDR低甲基化。FOXP 3+细胞主要见于TSDR低甲基化病例。TSDR低甲基化的ATL细胞比TSDR甲基化的ATL细胞表现出更强的抑制功能。因此，FOXP 3基因的表观遗传学分析鉴定了在异质性ATL中具有Treg特性的不同亚型。此外，我们观察到TSDR的低甲基化与ATL的不良结局相关。这些结果表明，TSDR的DNA甲基化状态是定义这种异质性疾病和预测ATL患者预后的重要标志。Cancer Immunol Res; 4（2）; 136-45.©2015 AACR.
A subtype of adult T-cell leukemia cells can be distinguished based on the hypomethylated state of their FOXP3 gene. These cells have Treg properties, and the patients have a poor prognosis. 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. Cancer Immunol Res; 4(2); 136–45. ©2015 AACR.