Wada Yuji, Naito Tadasuke, Fukushima Takuya, Saito Mineki
Department of Microbiology, Kawasaki Medical School, Kurashiki, Okayama, Japan.
Laboratory of Hematoimmunology, Graduate School of Health Sciences, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan.
Virol J. 2024 Dec 4;21(1):316. doi: 10.1186/s12985-024-02590-w.
Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic virus that causes malignant adult T-cell leukemia/lymphoma (ATL). Patients infected with HTLV-1 are considered HTLV-1 carriers, and a small proportion of patients progress to life-threatening ATL after a long asymptomatic phase. No antiviral agent or preventive vaccine specific for HTLV-1 infection is established in current situation. For development of countermeasures to combat HTLV-1 infection and ATL, it is essential to expand our knowledge about their pathogenesis. Recently, AlkB homolog (ALKBH) family have been shown to participate in the oncogenesis of various cancer types.
To investigate the potential role of ALKBH family members in the pathogenesis of ATL, we analyzed their gene expression dynamics in HTLV-1-infected T-cell lines and peripheral blood mononuclear cell-derived clinical specimens obtained from asymptomatic HTLV-1 carriers and patients with acute-type ATL. Epigenetic analysis was performed to dissect the mechanisms of ALKBH3 gene regulation using cultivated cells and a public dataset.
The mRNA expression levels of ALKBH2 and ALKBH3 were significantly or suggestively decreased in asymptomatic HTLV-1 carriers, but reverted in acute-type ATL patients, correlating with HTLV-1 basic leucine zipper factor gene expression. Intriguingly, the pre-mRNA expression of ALKBH2 and ALKBH3 was significantly suppressed in patients infected with HTLV-1, but not in healthy controls. Epigenetic analysis was performed to dissect the mechanisms of ALKBH3 gene regulation. In vitro analysis suggested a possible relationship between DNA methylation and ALKBH3 gene expression. Investigation of a public dataset revealed that specific CpG sites exhibited characteristically regulated methylation states in HTLV-1-infected T-cell subsets.
We discovered dynamically regulated patterns of ALKBH2 and ALKBH3 gene expression in patients infected with HTLV-1, and specific CpG sites epigenetically regulated by HTLV-1 infection. This study provides novel insights into HTLV-1 infection and contributes to the elucidation of ATL pathogenesis.
人类嗜T淋巴细胞病毒1型（HTLV-1）是一种致癌病毒，可导致成人恶性T细胞白血病/淋巴瘤（ATL）。感染HTLV-1的患者被视为HTLV-1携带者，一小部分患者在长期无症状期后会发展为危及生命的ATL。目前尚未建立针对HTLV-1感染的抗病毒药物或预防性疫苗。为了开发对抗HTLV-1感染和ATL的对策，扩大我们对其发病机制的了解至关重要。最近，AlkB同源物（ALKBH）家族已被证明参与多种癌症类型的肿瘤发生。
为了研究ALKBH家族成员在ATL发病机制中的潜在作用，我们分析了它们在HTLV-1感染的T细胞系以及从无症状HTLV-1携带者和急性型ATL患者获得的外周血单个核细胞衍生临床标本中的基因表达动态。使用培养细胞和公共数据集进行表观遗传分析，以剖析ALKBH3基因调控的机制。
在无症状HTLV-1携带者中，ALKBH2和ALKBH3的mRNA表达水平显著或提示性降低，但在急性型ATL患者中恢复，与HTLV-1碱性亮氨酸拉链因子基因表达相关。有趣的是，在感染HTLV-1的患者中，ALKBH2和ALKBH3的前体mRNA表达显著受到抑制，但在健康对照中未受抑制。进行表观遗传分析以剖析ALKBH3基因调控的机制。体外分析表明DNA甲基化与ALKBH3基因表达之间可能存在关系。对公共数据集的研究表明，特定的CpG位点在HTLV-1感染的T细胞亚群中表现出特征性调节的甲基化状态。
我们发现了感染HTLV-1的患者中ALKBH2和ALKBH3基因表达的动态调节模式，以及受HTLV-1感染表观遗传调控的特定CpG位点。本研究为HTLV-1感染提供了新的见解，并有助于阐明ATL的发病机制。
