Evaluation of ALKBH2 and ALKBH3 gene regulation in patients with adult T-cell leukemia/lymphoma

Abstract

Abstract Background 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. Methods 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. Results 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. Conclusion 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.

Keywords

• Human T-cell leukemia virus type 1
• Adult T-cell leukemia
• ALKBH2
• ALKBH3
• Epigenetics