Tumor relapse is the major cause of treatment failure in childhood acute lymphoblastic leukemia(ALL),yet the underlying mechanisms are still elusive.Here,we demonstrate that phosphoribosyl pyrophosphate synthetase 2(P...Tumor relapse is the major cause of treatment failure in childhood acute lymphoblastic leukemia(ALL),yet the underlying mechanisms are still elusive.Here,we demonstrate that phosphoribosyl pyrophosphate synthetase 2(PRPS2)mutations drive ALL relapse through influencing PRPS1/2 hexamer stability.Ultra-deep sequencing was performed to identify PRPS2 mutations in ALL samples.The effects of PRPS2 mutations on cell survival,cell apoptosis,and drug resistance were evaluated.In vitro PRPS2 enzyme activity and ADP/GDP feedback inhibition of PRPS enzyme activity were assessed.Purine metabolites were analyzed by ultra-performance liquid-chromatography tandem mass spectrometry(UPLC–MS/MS).Integrating sequencing data with clinical information,we identified PRPS2 mutations only in relapsed childhood ALL with thiopurine therapy.Functional PRPS2 mutations mediated purine metabolism specifically on thiopurine treatment by influencing PRPS1/2 hexamer stability,leading to reduced nucleotide feedback inhibition of PRPS activity and enhanced thiopurine resistance.The 3-amino acid V103-G104-E105,the key difference between PRPS1 and PRPS2,insertion in PRPS2 caused severe steric clash to the interface of PRPS hexamer,leading to its low enzyme activity.In addition,we demonstrated that PRPS2 P173R increased thiopurine resistance in xenograft models.Our work describes a novel mechanism by which PRPS2 mutants drive childhood ALL relapse and highlights PRPS2 mutations as biomarkers for relapsed childhood ALL.展开更多
基金National Natural Science Foundation of China(81972341,81900158,81772663,81874078,82072896)Shanghai Municipal Science and Technology Commission(201409002700,19JC1413500,21XD1403100)+1 种基金Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(20161310)Pudong New Area Science&Technology Development Fund(PKJ2018-Y47).
文摘Tumor relapse is the major cause of treatment failure in childhood acute lymphoblastic leukemia(ALL),yet the underlying mechanisms are still elusive.Here,we demonstrate that phosphoribosyl pyrophosphate synthetase 2(PRPS2)mutations drive ALL relapse through influencing PRPS1/2 hexamer stability.Ultra-deep sequencing was performed to identify PRPS2 mutations in ALL samples.The effects of PRPS2 mutations on cell survival,cell apoptosis,and drug resistance were evaluated.In vitro PRPS2 enzyme activity and ADP/GDP feedback inhibition of PRPS enzyme activity were assessed.Purine metabolites were analyzed by ultra-performance liquid-chromatography tandem mass spectrometry(UPLC–MS/MS).Integrating sequencing data with clinical information,we identified PRPS2 mutations only in relapsed childhood ALL with thiopurine therapy.Functional PRPS2 mutations mediated purine metabolism specifically on thiopurine treatment by influencing PRPS1/2 hexamer stability,leading to reduced nucleotide feedback inhibition of PRPS activity and enhanced thiopurine resistance.The 3-amino acid V103-G104-E105,the key difference between PRPS1 and PRPS2,insertion in PRPS2 caused severe steric clash to the interface of PRPS hexamer,leading to its low enzyme activity.In addition,we demonstrated that PRPS2 P173R increased thiopurine resistance in xenograft models.Our work describes a novel mechanism by which PRPS2 mutants drive childhood ALL relapse and highlights PRPS2 mutations as biomarkers for relapsed childhood ALL.
