尽管针对急性髓系白血病的新疗法已经开发出来，但大多数患者的治疗效果仍然不佳，治疗方法的改进是迫切需要满足的需求。尽管促进分化的治疗方案已成功治疗急性早幼粒细胞白血病，但其在其他急性粒细胞白血病亚型中的作用仍需探索。在这里，我们鉴定并表征了两种赖氨酸脱乙酰酶抑制剂 CM-444 和 CM-1758，与其他商业组蛋白脱乙酰酶抑制剂不同，它们在低非细胞毒性剂量下表现出促进所有急性髓系白血病亚型骨髓分化的能力。分析 CM-444 和 CM-1758 处理后的乙酰基组揭示了参与增强子-启动子染色质调节复合物的非组蛋白的调节，包括溴结构域蛋白。这种乙酰化对于增强直接参与 CM-444/CM-1758 在急性髓系白血病中诱导的分化治疗的关键转录因子的表达至关重要。总之，这些化合物可能代表针对急性髓系白血病亚型的有效的基于分化的治疗药物，并具有治疗急性髓系白血病的潜在机制。© 2024。作者。

Despite the development of novel therapies for acute myeloid leukemia, outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need. Although treatment regimens promoting differentiation have succeeded in the treatment of acute promyelocytic leukemia, their role in other acute myeloid leukemia subtypes needs to be explored. Here we identify and characterize two lysine deacetylase inhibitors, CM-444 and CM-1758, exhibiting the capacity to promote myeloid differentiation in all acute myeloid leukemia subtypes at low non-cytotoxic doses, unlike other commercial histone deacetylase inhibitors. Analyzing the acetylome after CM-444 and CM-1758 treatment reveals modulation of non-histone proteins involved in the enhancer-promoter chromatin regulatory complex, including bromodomain proteins. This acetylation is essential for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444/CM-1758 in acute myeloid leukemia. In summary, these compounds may represent effective differentiation-based therapeutic agents across acute myeloid leukemia subtypes with a potential mechanism for the treatment of acute myeloid leukemia.© 2024. The Author(s).