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Inhibiting EZH1\/2 suppresses ATLL through epigenetic modulation; however, the diverse genetic background of ATLL precludes its mode of action from being clearly elucidated. We conducted single\u2010cell RNA sequencing (scRNA\u2010seq) of primary ATLL cells and identified an epigenetic regulative axis. First, flow cytometry showed that the proliferative potential of CADM1<jats:sup>+<\/jats:sup> HTLV\u20101\u2010infected cells ranges from stable to treatment\u2010required. Second, scRNA\u2010seq identified a CCR4<jats:sup>+<\/jats:sup>CD48<jats:sup>\u2212<\/jats:sup> cluster, the population of which increased in treatment\u2010required patients. In silico promoter analysis of this cluster identified a transcription factor YY1 as a candidate regulator. Intracellular flow cytometry confirmed that YY1 and EZH2 were upregulated in acute\u2010type. By contrast, MLH1 but not MSH2 within CADM1<jats:sup>+<\/jats:sup> cells was downregulated in remitted ATLL (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05), suggesting that MLH1 is associated with YY1\/EZH2. Notably, lentiviral YY1 knockdown and the EZH1\/2 inhibitor valemetostat downregulated MLH1 in ATLL cell lines and primary ATLL cells. Finally, knockdown of YY1 or MLH1 suppressed the proliferation of ATLL cells. Our findings suggest that YY1\/EZH2 overexpression in the ATLL subpopulation defines aggressiveness and that MLH1 downregulation through YY1\/EZH2 inhibition may be an effective treatment for aggressive ATLL.<\/jats:p>","DOI":"10.1111\/cas.70095","type":"journal-article","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T23:19:32Z","timestamp":1747091972000},"page":"2163-2175","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Upregulation of <scp>YY1<\/scp>\/<scp>EZH2<\/scp> and <scp>MLH1<\/scp> as Therapeutic Targets for Adult T\u2010Cell Leukemia\/Lymphoma"],"prefix":"10.1111","volume":"116","author":[{"given":"Takuya","family":"Shimizu","sequence":"first","affiliation":[{"name":"Department of Hematology Kyoto University Graduate School of Medicine  Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2085-6151","authenticated-orcid":false,"given":"Takero","family":"Shindo","sequence":"additional","affiliation":[{"name":"Department of Hematology Kyoto University Graduate School of Medicine  Kyoto Japan"},{"name":"Department of Hematology\/Oncology Hiroshima University Research Institute for Radiation Biology and Medicine  Hiroshima Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanako","family":"Ogawa","sequence":"additional","affiliation":[{"name":"CyberomiX, Inc.  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