Epigenetic modifications, particularly through methylation of DNA packaging histones, play a pivotal role in controlling gene expression. Aberrant patterns of histone methylation have been associated with the development and progression of hematological malignancies. Unraveling the impact of aberrant histone marks on gene expression and leukemogenesis has spurred a concerted effort to develop clinically effective epigenetic therapies. In malignancies associated with the accumulation of histone H3 lysine trimethylation (H3K27me3), one such intervention involves preventing the deposition of this repressive histone mark by inhibiting the histone-modifying enzymes EZH1 and EZH2. While inhibition of EZH1/2 has demonstrated efficacy in both preclinical studies and clinical trials in various cancers, studies delineating the dynamic effect of EZH1/2 inhibition on H3K27me3 and disease relapse in clinical samples are lacking. In a recent publication, Yamagishi et al. explore how responses of a patient with adult T-cell leukemia/lymphoma to valemetostat, an EZH1/2 inhibitor, are associated with changes in H3K27me3, chromatin accessibility and gene expression, and how these changes can be circumvented in relapsed disease.

中文翻译：

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解开成人T细胞白血病/淋巴瘤的表观遗传秘密：深入研究EZH1/2抑制的机制和影响

表观遗传修饰，特别是通过 DNA 包装组蛋白的甲基化，在控制基因表达中发挥着关键作用。组蛋白甲基化的异常模式与血液恶性肿瘤的发生和进展有关。揭示异常组蛋白标记对基因表达和白血病发生的影响促使人们共同努力开发临床有效的表观遗传疗法。在与组蛋白 H3 赖氨酸三甲基化 (H3K27me3) 积累相关的恶性肿瘤中，此类干预措施之一是通过抑制组蛋白修饰酶 EZH1 和 EZH2 来防止这种抑制性组蛋白标记的沉积。虽然 EZH1/2 的抑制已在各种癌症的临床前研究和临床试验中证明有效，但缺乏描述 EZH1/2 抑制对 H3K27me3 的动态影响和临床样本中疾病复发的研究。在最近的出版物中，Yamagishi等人。探索成人 T 细胞白血病/淋巴瘤患者对 EZH1/2 抑制剂 valemetostat 的反应如何与 H3K27me3、染色质可及性和基因表达的变化相关，以及如何在复发性疾病中规避这些变化。