Acute myeloid leukemia (AML) is a heterogeneous myeloid neoplasm with poor clinical outcome, despite the great progress in treatment in recent years. The selective Bcl-2 inhibitor venetoclax (ABT-199) in combination therapy has been approved for the treatment of newly diagnosed AML patients who are ineligible for intensive chemotherapy, but resistance can be acquired through the upregulation of alternative antiapoptotic proteins. Here, we reported that a newly emerged histone deacetylase inhibitor, chidamide (CS055), at low-cytotoxicity dose enhanced the anti-AML activity of ABT-199, while sparing normal hematopoietic progenitor cells. Moreover, we also found that chidamide showed a superior resensitization effect than romidepsin in potentiation of ABT-199 lethality. Inhibition of multiple HDACs rather than some single component might be required. The combination therapy was also effective in primary AML blasts and stem/progenitor cells regardless of disease status and genetic aberrance, as well as in a patient-derived xenograft model carrying FLT3-ITD mutation. Mechanistically, CS055 promoted leukemia suppression through DNA double-strand break and altered unbalance of anti- and pro-apoptotic proteins (e.g., Mcl-1 and Bcl-xL downregulation, and Bim upregulation). Taken together, these results show the high therapeutic potential of ABT-199/CS055 combination in AML treatment, representing a potent and alternative salvage therapy for the treatment of relapsed and refractory patients with AML.

急性髓系白血病（AML）是一种异质性髓系肿瘤，尽管近年来治疗取得了巨大进展，但临床结果不佳。联合治疗中的选择性 Bcl-2 抑制剂 Venetoclax (ABT-199) 已被批准用于治疗不适合强化化疗的新诊断 AML 患者，但可通过替代抗凋亡蛋白的上调获得耐药性。在这里，我们报道了一种新出现的组蛋白脱乙酰酶抑制剂西达本胺 (CS055)，在低细胞毒性剂量下增强了 ABT-199 的抗 AML 活性，同时不影响正常造血祖细胞。此外，我们还发现西达本胺在增强 ABT-199 致死率方面表现出比罗米地辛更好的再敏作用。可能需要抑制多个 HDAC，而不是某些单一成分。无论疾病状态和遗传异常如何，该联合疗法对原发性 AML 母细胞和干细胞/祖细胞以及携带 FLT3-ITD 突变的患者来源的异种移植模型也有效。从机制上讲，CS055 通过 DNA 双链断裂和改变抗凋亡蛋白和促凋亡蛋白的不平衡（例如 Mcl-1 和 Bcl-xL 下调以及 Bim 上调）促进白血病抑制。总而言之，这些结果表明 ABT-199/CS055 组合在 AML 治疗中具有很高的治疗潜力，代表了治疗复发性和难治性 AML 患者的一种有效的替代挽救疗法。