Erythroleukemia is caused by the uncontrolled multiplication of immature erythroid progenitor cells which fail to differentiate into erythrocytes. By directly targeting this class of malignant cells, the induction of terminal erythroid differentiation represents a vital therapeutic strategy for this disease. Erythroid differentiation involves the execution of a well-orchestrated gene expression program in which epigenetic enzymes play critical roles. In order to identify novel epigenetic mediators of differentiation, this study explores the effects of multiple, highly specific, epigenetic enzyme inhibitors, in murine and human erythroleukemia cell lines. We used a group of compounds designed to uniquely target the following epigenetic enzymes: G9a/GLP, EZH1/2, SMYD2, PRMT3, WDR5, SETD7, SUV420H1 and DOT1L. The majority of the probes had a negative impact on both cell proliferation and differentiation. On the contrary, one of the compounds, A-366, demonstrated the opposite effect by promoting erythroid differentiation of both cell models. A-366 is a selective inhibitor of the G9a methyltransferase and the chromatin reader Spindlin1. Investigation of the molecular mechanism of action revealed that A-366 forced cells to exit from the cell cycle, a fact that favored erythroid differentiation. Further analysis led to the identification of a group of genes that mediate the A-366 effects and include CDK2, CDK4 and CDK6. A-366, a selective inhibitor of G9a and Spindlin1, demonstrates a compelling role in the erythroid maturation process by promoting differentiation, a fact that is highly beneficial for patients suffering from erythroleukemia. In conclusion, this data calls for further investigation towards the delivery of epigenetic drugs and especially A-366 in hematopoietic disorders.

中文翻译：

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与培养物中的化学诱导剂共同暴露时，组蛋白甲基转移酶抑制剂A-366可增强红白血病细胞中的血红蛋白表达

红细胞白血病是由未成熟的红系祖细胞的失控增殖引起的，该细胞无法分化为红细胞。通过直接靶向这类恶性细胞，最终红系分化的诱导代表了该疾病的重要治疗策略。红系分化涉及执行精心安排的基因表达程序，其中表观遗传酶发挥关键作用。为了鉴定新的分化表观遗传介体，本研究探索了多种高度特异性的表观遗传酶抑制剂在鼠和人红白血病细胞系中的作用。我们使用了一组专门针对以下表观遗传酶的化合物：G9a / GLP，EZH1 / 2，SMYD2，PRMT3，WDR5，SETD7，SUV420H1和DOT1L。大多数探针对细胞增殖和分化均具有负面影响。相反，其中一种化合物A-366通过促进两种细胞模型的类红细胞分化而显示出相反的作用。A-366是G9a甲基转移酶和染色质阅读器Spindlin1的选择性抑制剂。对分子作用机理的研究表明，A-366迫使细胞退出细胞周期，这有助于类红细胞分化。进一步的分析导致鉴定出一组介导A-366效应的基因，包括CDK2，CDK4和CDK6。A-366是G9a和Spindlin1的选择性抑制剂，通过促进分化而在红系成熟过程中表现出令人信服的作用，这一事实对患有红白血病的患者非常有益。结论，