Chromatin remodeling enhances MAP3K8 expression in HAM: a key pathogenesis for therapeutic intervention

Makoto Nakashima, Kaho Nagai, Naoki Takao, Natsumi Araya, Yuuta Kuze, Jun Mizuike, Shu Tosaka, Satoko Aratani, Naoko Yagishita, Erika Horibe, Toshiki Watanabe, Tomoo Sato, Yasuhito Nannya, Yutaka Suzuki, Kaoru Uchimaru, Makoto Yamagishi () and Yoshihisa Yamano ()
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Makoto Nakashima: St. Marianna University School of Medicine
Kaho Nagai: University of Tokyo
Naoki Takao: St. Marianna University School of Medicine
Natsumi Araya: St. Marianna University School of Medicine
Yuuta Kuze: The University of Tokyo
Jun Mizuike: University of Tokyo
Shu Tosaka: University of Tokyo
Satoko Aratani: St. Marianna University School of Medicine
Naoko Yagishita: St. Marianna University School of Medicine
Erika Horibe: St. Marianna University School of Medicine
Toshiki Watanabe: St. Marianna University School of Medicine
Tomoo Sato: St. Marianna University School of Medicine
Yasuhito Nannya: the University of Tokyo
Yutaka Suzuki: The University of Tokyo
Kaoru Uchimaru: University of Tokyo
Makoto Yamagishi: University of Tokyo
Yoshihisa Yamano: St. Marianna University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy (HAM) is a debilitating neuroinflammatory disease with no available effective treatments. A hallmark of HAM is the transformation of HTLV-1-infected cells into T helper type 1 (Th1)-like cells, characterized by excessive interferon (IFN)-γ production that drives chronic inflammation. However, the molecular mechanisms fuel this aberrant Th1-like transformation and sustained inflammation remain poorly understood. We hypothesized that HAM-characteristic chromatin remodeling plays a pivotal role in the overexpression of key genes driving inflammatory pathogenesis. Using transcriptomic analysis, chromatin accessibility profiling, and biomarker evaluations across HTLV-1-related diseases, we identify MAP3K8 as a key gene that defines the unique inflammatory profile of HAM. MAP3K8 overexpression promotes Th1-like differentiation and constitutively activates the MEK-ERK signaling pathway. Furthermore, we elucidate the mechanism by which HTLV-1 Tax, Fosl2, and c-Jun collaboratively induce HAM-characteristic chromatin remodeling at the enhancer region of the MAP3K8 locus. Crucially, we demonstrate that mitogen-activated protein kinase kinase (MEK) inhibitors effectively suppress the MAP3K8-MEK signaling cascade and significantly mitigated inflammatory pathogenesis in an ex vivo culture assay. Our findings provide critical insights into the virus-host interactions underpinning HAM and propose the MAP3K8-MEK-ERK axis as a promising therapeutic target for this challenging condition.

Date: 2025
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DOI: 10.1038/s41467-025-64836-7

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