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 þ 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.

Semaphorin 4A Stabilizes Human Regulatory T Cell Phenotype via Plexin B1

“…With higher numbers of CD25-expressing cells among HuT102 cells we observe a higher Foxp3 expression. The variance in Foxp3 expression between primary adult T cell leukemia lymphoma cells and different adult T cell leukemia lymphoma cell lines has been reported previously (28). Low Sema4A expression on HuT102 cells was accompanied by high Plexin B1 expression ( Fig.…”

“…It has been shown previously that HuT78 and HuT102 cells display a mature Th phenotype expressing CD3 (25,26) and CD4 molecules (26) and secreting a variety of proinflammatory and Th-type cytokines (27). One of these cell lines, HuT102, was previously shown to express the Treg cell marker Foxp3 (28).…”

Hydroquinone-induced FOXP3-ADAM17-Lyn-Akt-p21 signaling axis promotes malignant progression of human leukemia U937 cells

“…Given the limits of the methods and assays used in the present study, the involvement of FOXP3/ ADAM17/Lyn/Akt/p21 signaling axis in the in vivo effects of HQ needs to be investigated further. Recent studies suggest that hypomethylation of TSDR region in FOXP3 gene which causes up-regulation of FOXP3 expression is a hallmark for predicting worse prognosis of patients with adult T cell leukemia (Shimazu et al 2016). Moreover, Akt activation is found to promote progression of adult T cell leukemia and AML (Grandage et al 2005;Fukuda et al 2005;Fig.…”

The Role of HTLV-1 in Alteration of Immune Regulation Through Regulatory T Cell Dysfunction and Exosomal Manipulation

“…This has led to a prevailing theory suggesting that ATLL results from the clonal expansion of infected regulatory T cells, resulting in a largely suppressive immune environment that allows for leukemic cells to escape immune detection (Chen et al, 2006;. Indeed, isolated ATLL patient Tregs suppress as well as Tregs from a ND (Chen et al, 2006; and have hypomethylation of the FoxP3 TSDR (Shimazu et al, 2016).…”

“…Additionally, Tax participates in silencing of the SHP-1 promoter in a process termed Tax-induced promoter silencing (TIPS) by complexing with HDAC, a histone deacetylase, and leading to increased methylation (Cheng et al, 2007;Nakase et al, 2009). Of note, Tax expression is low to absent in PBMCs from patients with ATLL, which are characterized by high FoxP3 expression, hypomethylation of the TSDR, and Treg-like suppressive abilities (Araya et al, 2011;Shimazu et al, 2016;. HTLV-1 Tax has multiple binding factors, including CREB, CBP/p300, and Ets1, all of which are implicated in maintenance of Foxp3 expression (Boxus et al, 2008).…”