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...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.展开更多
The p53 pathway is a highly complex signaling network including several key regulators.HAUSP is a critical component of the p53 pathway acting as a deubiquitinase for both p53 and its key repressor Mdm2.Here,we identi...The p53 pathway is a highly complex signaling network including several key regulators.HAUSP is a critical component of the p53 pathway acting as a deubiquitinase for both p53 and its key repressor Mdm2.Here,we identified a novel HAUSP-interacting protein,HLA-B-associated transcript 3(Bat3)and found it to be capable of inducing p53 stabilization and activation via a HAUSP-dependent mechanism,resulting in cell growth inhibition.Surprisingly,the deubiquitylating enzymatic activity of HAUSP was not required for this phenomenon.Co-immunoprecipitation showed that p53 coexisted in a complex with Bat3 and HAUSP in vivo,and HAUSP may serve as a binding mediator to enhance the interaction between p53 and Bat3.Further studies revealed that formation of this three-protein complex interfered with the binding of p53 to its proteasome receptor S5a and promoted the accumulation of p53 in nucleus.Notably,Mdm2 protein abundance is also regulated by Bat3 in the presence of HAUSP.Overexpression of Bat3 and HAUSP increases Mdm2 protein levels without influencing the p53–Mdm2 interaction and Mdm2-mediated p53 ubiquitination,indicating that Bat3–HAUSP-mediated protein stabilization is not specific to p53 and different mechanisms may be involved in Bat3-mediated regulation of p53–Mdm2 pathway.Together,our study unravels a novel mechanism by which p53 is stabilized and activated by HAUSP-mediated interaction with Bat3 and implies that Bat3 might function as a tumor suppressor through the stabilization of p53.展开更多
基金supported by grants from the National Natural Science Foundation of China(82074067)Natural Science Foundation of Jiangsu Province China(BK20181419,China)Natural Foundation of Jiangsu Higher Education Institutions of China(19KJA310006)。
文摘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.
基金This work was supported by the National Natural Science Foundation of China(31500703,31371351,and 31671488)the Program for New Century Excellent Talents in University of China(NCET-09-0737).
文摘The p53 pathway is a highly complex signaling network including several key regulators.HAUSP is a critical component of the p53 pathway acting as a deubiquitinase for both p53 and its key repressor Mdm2.Here,we identified a novel HAUSP-interacting protein,HLA-B-associated transcript 3(Bat3)and found it to be capable of inducing p53 stabilization and activation via a HAUSP-dependent mechanism,resulting in cell growth inhibition.Surprisingly,the deubiquitylating enzymatic activity of HAUSP was not required for this phenomenon.Co-immunoprecipitation showed that p53 coexisted in a complex with Bat3 and HAUSP in vivo,and HAUSP may serve as a binding mediator to enhance the interaction between p53 and Bat3.Further studies revealed that formation of this three-protein complex interfered with the binding of p53 to its proteasome receptor S5a and promoted the accumulation of p53 in nucleus.Notably,Mdm2 protein abundance is also regulated by Bat3 in the presence of HAUSP.Overexpression of Bat3 and HAUSP increases Mdm2 protein levels without influencing the p53–Mdm2 interaction and Mdm2-mediated p53 ubiquitination,indicating that Bat3–HAUSP-mediated protein stabilization is not specific to p53 and different mechanisms may be involved in Bat3-mediated regulation of p53–Mdm2 pathway.Together,our study unravels a novel mechanism by which p53 is stabilized and activated by HAUSP-mediated interaction with Bat3 and implies that Bat3 might function as a tumor suppressor through the stabilization of p53.