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Although individual interactions between Tax and host factors have been investigated, their global network and functional impact remain unclear. In this study, we performed proteomic analyses of Tax\u2010associated complexes in HTLV\u20101\u2013infected T\u2010cells and mapped interactions between host factors and Tax. In addition to known nuclear factor kappa B (NF\u2010\u03baB) regulators, we identified the transcription factor interferon regulatory factor 4 (IRF4) as a novel interactor. Co\u2010immunoprecipitation experiments confirmed Tax\u2013IRF4 binding, and chromatin profiling revealed that Tax reprograms genome\u2010wide IRF4 occupancy. In infected T\u2010cells, IRF4 was enriched in super\u2010enhancer (SE) regions, where Tax, IRF4, and NF\u2010\u03baB factors colocalized at ATL\u2010related loci, and this was accompanied by histone acetylation changes and transcriptional activation. Functionally, Tax and IRF4 co\u2010expression cooperatively restructured chromatin accessibility and induced aberrant gene expression programs. Moreover, ATL\u2010associated IRF4 mutants (K59R, L70V, and S114N) partially reproduced Tax\u2010driven chromatin remodeling and transcriptional reprogramming, suggesting that convergent mechanisms drive leukemogenesis. Collectively, these findings demonstrate that Tax exploits IRF4 to establish a novel regulatory mechanism. This interaction drives widespread epigenomic reprogramming in HTLV\u20101\u2013infected T\u2010cells. Overall, our study underscores the central role of Tax in IRF4 exploitation to induce infection\u2010specific epigenomic changes, which offers novel insights into ATL pathogenesis and therapeutic strategies.<\/jats:p>","DOI":"10.1111\/cas.70349","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T13:08:05Z","timestamp":1772975285000},"page":"1497-1509","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>HTLV<\/scp>\n                    \u20101 Tax Reshapes the\n                    <scp>DNA<\/scp>\n                    \u2010Binding Pattern of Transcription Factor\n                    <scp>IRF4<\/scp>\n                    and Disrupts Host Gene Regulation"],"prefix":"10.1111","volume":"117","author":[{"given":"Shu","family":"Tosaka","sequence":"first","affiliation":[{"name":"Laboratory of Viral Oncology and Genomics, Department of Computational Biology and Medical Sciences Graduate School of Frontier Sciences, The University of Tokyo  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Mizuike","sequence":"additional","affiliation":[{"name":"Laboratory of Tumor Cell Biology, Department of Computational Biology and Medical Sciences Graduate School of Frontier Sciences, The University of Tokyo  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motomu","family":"Yano","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Oncology and Genomics, Department of Computational Biology and Medical Sciences Graduate School of Frontier Sciences, The University of Tokyo  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaoru","family":"Uchimaru","sequence":"additional","affiliation":[{"name":"Laboratory of Tumor Cell Biology, Department of Computational Biology and Medical Sciences Graduate School of Frontier Sciences, The University of Tokyo  Tokyo Japan"},{"name":"Showa Medical University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8142-4686","authenticated-orcid":false,"given":"Makoto","family":"Yamagishi","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Oncology and Genomics, Department of Computational Biology and Medical Sciences Graduate School of Frontier Sciences, The University of Tokyo  Tokyo 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