Upregulation of YY1/EZH2 and MLH1 as Therapeutic Targets for Adult T-Cell Leukemia/Lymphoma.

The clinical and genetic presentation of adult T-cell leukemia/lymphoma (ATLL) ranges from indolent to aggressive, making it difficult to identify common therapeutic targets. 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-cell RNA sequencing (scRNA-seq) of primary ATLL cells and identified an epigenetic regulative axis. First, flow cytometry showed that the proliferative potential of CADM1⁺ HTLV-1-infected cells ranges from stable to treatment-required. Second, scRNA-seq identified a CCR4⁺CD48^- cluster, the population of which increased in treatment-required 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-type. By contrast, MLH1 but not MSH2 within CADM1⁺ cells was downregulated in remitted ATLL (p < 0.05), 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.