Human T-cell leukemia virus type 1 (HTLV-1) is a human retrovirus that primarily infects CD4-positive T cells (immune cells). Approximately 5% of infected individuals develop serious diseases such as adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). HAM is an intractable neurological disease with no established treatment. Its pathology involves HTLV-1-infected T cells infiltrating the spinal cord, causing chronic inflammation that ultimately destroys neural tissue.
Associate Professor Makoto Yamagishi of the Graduate School of Frontier Sciences, the University of Tokyo, working with researchers such as Professor and Chairman Yoshihisa Yamano of the Department of Neurology, St. Marianna University School of Medicine and Dr. Makoto Nakashima of the Department of Rare Diseases Research, Intractable Disease Center, St. Marianna University School of Medicine, identified MAP3K8 as a central molecule that drives inflammation in HAM.
Furthermore, they revealed the mechanism by which MAP3K8 becomes overexpressed: through chromatin remodeling triggered by the viral factor HTLV-1 Tax. They showed that MEK inhibitors targeting the downstream MAP3K8-MEK-ERK pathway may have strong anti-inflammatory effects.
The researchers also compared the gene expression and chromatin structure data of HTLV-1-infected T cells across HTLV-1-related diseases, including HAM patients and ATL patients.
As a result, they found that HAM-specific chromatin structural abnormalities exist, with MAP3K8 showing the most striking changes among the affected genes. They also experimentally confirmed that MAP3K8 has inflammation-inducing ability.
This discovery may pave the way for developing new therapies for HAM, a disease with no established cure, in addition to other inflammatory diseases persistently driven by similar mechanisms. The study was published in Nature Communications.
Journal Information
Publication: Nature Communications
Title: Chromatin remodeling enhances MAP3K8 expression in HAM: a key pathogenesis for therapeutic intervention
DOI: 10.1038/s41467-025-64836-7
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