Novel epigenetic based differentiation therapy for Acute Myeloid Leukemia

We have identified and characterized two lysine (K) deacetylase inhibitors (DACi), CM-444 and CM-1758. These inhibitors demonstrate the ability to promote myeloid differentiation in all acute myeloid leukemia (AML) subtypes at low, non-cytotoxic doses, setting them apart from other commercially available histone deacetylase inhibitors (HDACi). Upon analysis of the acetylome following treatment with CM-444 and CM-1758, we observed modulation of non-histone proteins involved in the enhancer–promoter chromatin regulatory complex, including bromodomain proteins (BRDs). This acetylation is crucial for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444 and CM-1758 in AML. In summary, these compounds present promising potential as effective differentiation-based therapeutic agents across AML subtypes, offering a novel mechanism for the treatment of AML

我们已鉴定并表征了两种赖氨酸（K）脱乙酰酶抑制剂（DACi）：CM-444与CM-1758。相较于其他市售的组蛋白脱乙酰酶抑制剂（HDACi），此类抑制剂在低剂量且无细胞毒性的条件下，即可促进所有急性髓系白血病（AML）亚型的髓系分化，这一特性使其脱颖而出。通过对CM-444与CM-1758处理后的乙酰化修饰组进行分析，我们观察到参与增强子-启动子染色质调控复合物的非组蛋白发生了修饰调控，其中包括溴结构域蛋白（BRDs）。该乙酰化修饰对于增强关键转录因子的表达至关重要，而这些转录因子直接参与CM-444与CM-1758诱导的AML分化疗法。综上，这类化合物作为基于分化疗法的有效治疗试剂，在各AML亚型中展现出极具潜力的应用前景，为AML的治疗提供了全新的作用机制。