Heliangin acts as a covalent ligand of RPS2 that disrupts pre-rRNA metabolic processes in NPM1-mutated acute myeloid leukemia

Although NPM1 mutations are frequently found in acute myeloid leukemia patients, thera-peutic 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 differenti-ation. 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 elec-trophilic 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 fndings suggest a novel treatment strategy and lead compound for acute myeloid leukemia patients, especially those with NPM1 mutations.@ 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

In this study, it was found that heliangin, a natural sesquiterpene lactone, has favorable therapeutic effects on NPM1 mutant acute myeloid leukemia cells. It inhibits cell proliferation, induces apoptosis, causes cell cycle arrest, and promotes cell differentiation without apparent toxicity to normal hematogenous cells. The main target of heliangin in treating NPM1 mutant AML was found to be ribosomal protein S2, which disrupts pre-rRNA metabolic processes and leads to nucleolar stress, thereby regulating the ribosomal proteins-MDM2-p53 pathway. RPS2 plays a critical role in regulating the pre-rRNA metabolic pathway and may be a novel treatment target.