Leukemia stem cells (LSCs) are considered to be the root of relapse for acute myeloid leukemia (AML). Conventional chemotherapeutic drugs fail to eliminate LSCs. Therefore, new therapeutic strategies eliminating LSCs are urgently needed. Our results showed that low-dose Triptolide (TPL) enhanced the anti-AML activity of Idarubicin (IDA) in vitro against LSC-like cells (CD34 + CD38- KG1αand CD34 + CD38- kasumi-1 cells) and CD34+ primary AML cells, while sparing normal cells. Inspiringly, the combination treatment with low-dose TPL and IDA was also effective against CD34 + blasts from AML patients with FLT3-ITD mutation, which is an unfavorable risk factor for AML patients. Moreover, the combination of TPL and IDA induced a remarkable suppression of human leukemia growth in a xenograft mouse model. Mechanistically, the enhanced effect of low dose TPL on IDA against LSCs was attributed to inhibiting DNA damage repair response. Thus, our study may provide a theoretical basis to facilitate the development of a novel LSCs-targeting strategy for AML.

Graphical abstract

白血病干细胞（LSCs）被认为是急性髓系白血病（AML）复发的根源。常规化疗药物不能消除 LSC。因此，迫切需要消除 LSC 的新治疗策略。我们的研究结果表明，低剂量雷公藤内酯（TPL）在体外增强了伊达比星（IDA）对 LSC 样细胞（CD34 + CD38- KG1α 和 CD34 + CD38- kasumi-1 细胞）和 CD34 + 原代 AML 细胞的抗 AML 活性，同时保留正常细胞。令人鼓舞的是，低剂量 TPL 和 IDA 的联合治疗对来自具有 FLT3-ITD 突变的 AML 患者的 CD34 + 原始细胞也有效，这是 AML 患者的不利危险因素。此外，在异种移植小鼠模型中，TPL 和 IDA 的组合显着抑制了人类白血病的生长。机械地，低剂量 TPL 对 IDA 对 LSCs 的增强作用归因于抑制 DNA 损伤修复反应。因此，我们的研究可能为促进针对 AML 的新型 LSCs 靶向策略的开发提供理论基础。

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