文章：

抑制Zeste同源物增强子2可诱导急性髓系白血病小鼠模型中的原始细胞分化、损害移植能力并延长生存期

Inhibition of Enhancer of Zeste Homolog 2 Induces Blast Differentiation, Impairs Engraftment and Prolongs Survival in Murine Models of Acute Myeloid Leukemia

原文发布日期：29 January 2024

DOI: 10.3390/cancers16030569

类型: Article

开放获取: 是

英文摘要：

Background: Acute myeloid leukemia (AML) is the malignant proliferation of immature myeloid cells characterized by a block in differentiation. As such, novel therapeutic strategies to promote the differentiation of immature myeloid cells have been successful in AML, although these agents are targeted to a specific mutation that is only present in a subset of AML patients. In the current study, we show that targeting the epigenetic modifier enhancer of zeste homolog 2 (EZH2) can induce the differentiation of immature blast cells into a more mature myeloid phenotype and promote survival in AML murine models. Methods: The EZH2 inhibitor EPZ011989 (EPZ) was studied in AML cell lines, primary in AML cells and normal CD34+ stem cells. A pharmacodynamic assessment of H3K27me3; studies of differentiation, cell growth, and colony formation; and in vivo therapeutic studies including the influence on primary AML cell engraftment were also conducted. Results: EPZ inhibited H3K27me3 in AML cell lines and primary AML samples in vitro. EZH2 inhibition reduced colony formation in multiple AML cell lines and primary AML samples, while exhibiting no effect on colony formation in normal CD34+ stem cells. In AML cells, EPZ promoted phenotypic evidence of differentiation. Finally, the pretreatment of primary AML cells with EPZ significantly delayed engraftment and prolonged the overall survival when engrafted into immunodeficient mice. Conclusions: Despite evidence that EZH2 silencing in MDS/MPN can promote AML pathogenesis, our data demonstrate that the therapeutic inhibition of EZH2 in established AML has the potential to improve survival.

摘要翻译： 

背景：急性髓系白血病（AML）是一种以未成熟髓系细胞异常增殖为特征的恶性疾病，其分化过程受阻。因此，促进未成熟髓系细胞分化的新型治疗策略已在AML中取得成效，尽管这些药物仅针对特定突变，而该突变仅存在于部分AML患者中。本研究显示，靶向表观遗传修饰因子zeste同源物2增强子（EZH2）可诱导未成熟原始细胞分化为更成熟的髓系表型，并在AML小鼠模型中延长生存期。方法：在AML细胞系、原代AML细胞及正常CD34+干细胞中研究EZH2抑制剂EPZ011989（EPZ）。研究内容包括H3K27me3的药效学评估、分化、细胞生长和集落形成实验，以及体内治疗研究（包括对原代AML细胞植入的影响）。结果：EPZ在体外能抑制AML细胞系和原代AML样本中的H3K27me3。EZH2抑制可减少多种AML细胞系和原代AML样本的集落形成，但对正常CD34+干细胞的集落形成无影响。在AML细胞中，EPZ促进了分化的表型证据。最后，将经EPZ预处理的原代AML细胞植入免疫缺陷小鼠后，显著延迟了植入时间并延长了总生存期。结论：尽管有证据表明在MDS/MPN中沉默EZH2可能促进AML发病机制，但我们的数据证明，在已形成的AML中治疗性抑制EZH2具有改善生存的潜力。

原文链接：

Inhibition of Enhancer of Zeste Homolog 2 Induces Blast Differentiation, Impairs Engraftment and Prolongs Survival in Murine Models of Acute Myeloid Leukemia