Although NPM1 mutations are frequently found in acute myeloid leukemia patients, therapeutic strategies are scarce and unsuitable for those who cannot tolerate intensive chemotherapy. Here we demonstrated that heliangin, a natural sesquiterpene lactone, exerts favorable therapeutic responses in NPM1 mutant acute myeloid leukemia cells, with no apparent toxicity to normal hematogenous cells, by inhibiting their proliferation, inducing apoptosis, causing cell cycle arrest, and promoting differentiation. In-depth studies on its mode of action using quantitative thiol reactivity platform screening and subsequent molecular biology validation showed that the ribosomal protein S2 (RPS2) is the main target of heliangin in treating NPM1 mutant AML. Upon covalent binding to the C222 site of RPS2, the electrophilic moieties of heliangin disrupt pre-rRNA metabolic processes, leading to nucleolar stress, which in turn regulates the ribosomal proteins–MDM2–p53 pathway and stabilizes p53. Clinical data shows that the pre-rRNA metabolic pathway is dysregulated in acute myeloid leukemia patients with the NPM1 mutation, leading to a poor prognosis. We found that RPS2 plays a critical role in regulating this pathway and may be a novel treatment target. Our findings suggest a novel treatment strategy and lead compound for acute myeloid leukemia patients, especially those with NPM1 mutations.

尽管NPM1突变经常在急性髓性白血病患者中发现，但治疗策略很少且不适合那些不能耐受强化化疗的患者。在这里，我们证明了 heliangin 是一种天然倍半萜内酯，通过抑制其增殖、诱导细胞凋亡、导致细胞周期停滞和促进分化，对NPM1突变急性髓性白血病细胞产生良好的治疗反应，对正常造血细胞没有明显毒性。使用定量硫醇反应平台筛选和随后的分子生物学验证对其作用模式的深入研究表明，核糖体蛋白S2（RPS2）是核糖体治疗NPM1的主要靶点突变型 AML。在与 RPS2 的 C222 位点共价结合后，Heliangin 的亲电部分破坏了前 rRNA 代谢过程，导致核仁应激，进而调节核糖体蛋白-MDM2-p53 通路并稳定 p53。临床数据显示，携带NPM1突变的急性髓性白血病患者的前 rRNA 代谢通路失调，导致预后不良。我们发现 RPS2 在调节该通路中起着关键作用，可能是一个新的治疗靶点。我们的研究结果为急性髓性白血病患者，尤其是那些有NPM1突变的患者提出了一种新的治疗策略和先导化合物。