Liaoning Key Laboratory of Hematopoietic Stem Cell Transplantation and Translational Medicine, Second Hospital of Dalian Medical University, Dalian, China; Department of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Second Hospital of Dalian Medical University, Dalian, China.
College of Pharmacy, Dalian Medical University, Dalian, China.
Biochem Biophys Res Commun. 2023 Oct 1;675:155-161. doi: 10.1016/j.bbrc.2023.07.027. Epub 2023 Jul 16.
Acute myeloid leukemia (AML) is a heterogeneous disease and about one third of AML patients carry nucleophosmin (NPM1) mutation. Because 95% mutations give NPM1 an additional nuclear export signaling (NES) and dislocate NPM1 in cytoplasm (NPMc), relocating NPM1 in nucleus provide an innovative strategy for treating this type of AML. The nuclear export of NPM1 depends on the nuclear protein export receptor XPO1, which recognizes the NES sequence on NPM1. Homoharringtonine (HHT) is a first-line chemotherapy drug of AML, yet the exact mechanism of its anti-AML activity is elusive. In this study, we found that HHT can directly target XPO1 to its NES-binding cleft, bind to Cys528 of XPO1, and inhibits its nuclear transport function. In addition, HHT can block NPMc proteins nuclear export and thus make NPMc AML cells much more sensitive to HHT treatment. Furthermore, the sensitivity of NPMc AML cells to HHT is a universal phenomenon irrespective of the different genetic lesions of AML. Taken together, our findings suggest that XPO1 is a new target of HHT and provide a novel strategy for NPMc AML treatment.
急性髓系白血病（AML）是一种异质性疾病，约三分之一的 AML 患者携带核磷蛋白（NPM1）突变。因为 95%的突变会给 NPM1 增加一个额外的核输出信号（NES）并将 NPM1 易位到细胞质中（NPMc），所以将 NPM1 重新定位到核内为治疗这种类型的 AML 提供了一种创新的策略。NPM1 的核输出依赖于核蛋白输出受体 XPO1，它识别 NPM1 上的 NES 序列。高三尖杉酯碱（HHT）是 AML 的一线化疗药物，但它的抗 AML 活性的确切机制尚不清楚。在这项研究中，我们发现 HHT 可以直接靶向 XPO1 的 NES 结合裂隙，与 XPO1 的 Cys528 结合，并抑制其核转运功能。此外，HHT 可以阻断 NPMc 蛋白的核输出，从而使 NPMc AML 细胞对 HHT 治疗更加敏感。此外，NPMc AML 细胞对 HHT 的敏感性是一种普遍现象，与 AML 的不同遗传病变无关。总之，我们的研究结果表明，XPO1 是 HHT 的一个新靶点，并为 NPMc AML 的治疗提供了一种新策略。
