Shimizu Takuya, Shindo Takero, Ogawa Hanako, Teranaka Kaori, Watanabe Akira, Takaori-Kondo Akifumi
Department of Hematology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Hematology/Oncology, Hiroshima University Research Institute for Radiation Biology and Medicine, Hiroshima, Japan.
Cancer Sci. 2025 Aug;116(8):2163-2175. doi: 10.1111/cas.70095. Epub 2025 May 12.
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 CCR4CD48 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.
成人T细胞白血病/淋巴瘤（ATLL）的临床和基因表现从惰性到侵袭性不等，这使得难以确定常见的治疗靶点。抑制EZH1/2可通过表观遗传调控抑制ATLL；然而，ATLL多样的基因背景使其作用模式难以得到清晰阐释。我们对原发性ATLL细胞进行了单细胞RNA测序（scRNA-seq），并确定了一个表观遗传调控轴。首先，流式细胞术显示CADM1 HTLV-1感染细胞的增殖潜力从稳定到需要治疗不等。其次，scRNA-seq确定了一个CCR4CD48簇，在需要治疗的患者中该簇的细胞数量增加。对该簇进行的计算机启动子分析确定转录因子YY1为候选调节因子。细胞内流式细胞术证实，YY1和EZH2在急性型中上调。相比之下，缓解期ATLL中CADM1细胞内的MLH1而非MSH2下调（p < 0.05），这表明MLH1与YY1/EZH2相关。值得注意的是，慢病毒介导的YY1敲低和EZH1/2抑制剂瓦勒莫司他在ATLL细胞系和原发性ATLL细胞中下调了MLH1。最后，YY1或MLH1的敲低抑制了ATLL细胞的增殖。我们的研究结果表明，ATLL亚群中YY1/EZH2的过表达决定了侵袭性，通过抑制YY1/EZH2下调MLH1可能是侵袭性ATLL的一种有效治疗方法。
