EZH2 Inhibition and Myeloid Risk: A Feature of On-Target Biology.

The most frequently reported SPMs were myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

最常报告的SPM是骨髓增生异常综合征（MDS）和急性髓细胞性白血病（AML）。

Although this finding may be interpreted as an idiosyncratic liability of a single agent, the biology of EZH2 suggests a broader, target-driven risk.

尽管这一发现可能被解释为单一药物的特异性责任，但EZH2的生物学特性表明存在更广泛的、基于靶点的风险。

EZH2 functions in a context-dependent manner as both an oncogene and a tumor suppressor.

EZH2在不同情况下既可以作为致癌基因，也可以作为肿瘤抑制基因发挥作用。

Gain-of-function mutations drive transformation in germinal center B-cell lymphomas, whereas loss-of-function alterations impair hematopoietic stem cell differentiation and are recurrent in myeloid malignancies, including MDS and AML.

获得功能突变驱动了生发中心B细胞淋巴瘤的转化，而功能丧失的改变则损害了造血干细胞的分化，并且在包括MDS和AML在内的髓系恶性肿瘤中反复出现。

In selected solid tumor contexts, such as specific subtypes of medulloblastoma, EZH2 loss can likewise promote tumorigenesis.

在某些实体瘤环境中，例如特定亚型的髓母细胞瘤，EZH2的丧失也可以促进肿瘤发生。

These observations raise concern that chronic pharmacologic inhibition of EZH2 may phenocopy loss-of-function states that initiate myeloid neoplasia.

这些观察结果引发了对慢性药理学抑制EZH2可能模拟功能丧失状态并引发髓系肿瘤的担忧。

We argue that the withdrawal of tazemetostat exposes a fundamental vulnerability in the development of epigenetic therapies: Target validation has focused on tumor-intrinsic effects while underweighting consequences in normal stem cell compartments.

我们认为tazemetostat的撤回暴露了表观遗传治疗开发中的一个根本性弱点：靶点验证集中在肿瘤内在效应上，而对正常干细胞群落的后果重视不足。

This issue is particularly relevant for ongoing phase III programs in prostate cancer, in which prolonged exposure may amplify latency-dependent risks.

这一问题对于正在进行的前列腺癌III期项目尤为重要，在这些项目中，长期暴露可能会放大与潜伏期相关的风险。

We propose changes to preclinical safety assessment, trial design, and pharmacovigilance to mitigate predictable, target-mediated toxicities.

我们建议对临床前安全性评估、试验设计和药物警戒进行改变，以减轻可预测的、靶向介导的毒性。