Objective:To study the correlation of PRPS1 and JAB1 expression in the bone marrow tissue of acute leukemia with the apoptosis and invasion of tumor cells.Methods:Patients who were diagnosed with acute leukemia by bon...Objective:To study the correlation of PRPS1 and JAB1 expression in the bone marrow tissue of acute leukemia with the apoptosis and invasion of tumor cells.Methods:Patients who were diagnosed with acute leukemia by bone marrow aspiration biopsy in Edong medical group Huangshi central hospital between February 2015 and December 2017 were selected as the AL group of the research, and patients who received bone marrow aspiration biopsy and were without significant abnormality in Edong medical group Huangshi central hospital during the same period were selected as the control group of the research. RNA was extracted to determine the mRNA expression of PRPS1, JAB1, apoptosis genes and invasion genes, and protein was extracted to determine the protein expression of PRPS1 and JAB1.Results:Both mRNA expression and protein expression of PRPS1 and JAB1 in bone marrow tissues of AL group were significantly higher than those of control group;AuroraA, Bcl-2,β-catenin, MMP2, MMP9, N-cadherin and Msi2 mRNA expression in bone marrow tissues of AL group were significantly higher than those of control group whereas Bax, C/EBP , RUNX3 and TIMP3 mRNA expression were significantly lower than those of control group, and the PRPS1 and JAB1 mRNA expression in bone marrow tissues of AL group were positively correlated with AuroraA, Bcl-2,β-catenin, MMP2, MMP9, N-cadherin and Msi2 mRNA expression, and negatively correlated with Bax, C/EBP , RUNX3 and TIMP3 mRNA expression.Conclusion:The high expression of PRPS1 and JAB1 in the bone marrow tissue of acute leukemia can inhibit cell apoptosis and promote cell invasion.展开更多
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
文摘Objective:To study the correlation of PRPS1 and JAB1 expression in the bone marrow tissue of acute leukemia with the apoptosis and invasion of tumor cells.Methods:Patients who were diagnosed with acute leukemia by bone marrow aspiration biopsy in Edong medical group Huangshi central hospital between February 2015 and December 2017 were selected as the AL group of the research, and patients who received bone marrow aspiration biopsy and were without significant abnormality in Edong medical group Huangshi central hospital during the same period were selected as the control group of the research. RNA was extracted to determine the mRNA expression of PRPS1, JAB1, apoptosis genes and invasion genes, and protein was extracted to determine the protein expression of PRPS1 and JAB1.Results:Both mRNA expression and protein expression of PRPS1 and JAB1 in bone marrow tissues of AL group were significantly higher than those of control group;AuroraA, Bcl-2,β-catenin, MMP2, MMP9, N-cadherin and Msi2 mRNA expression in bone marrow tissues of AL group were significantly higher than those of control group whereas Bax, C/EBP , RUNX3 and TIMP3 mRNA expression were significantly lower than those of control group, and the PRPS1 and JAB1 mRNA expression in bone marrow tissues of AL group were positively correlated with AuroraA, Bcl-2,β-catenin, MMP2, MMP9, N-cadherin and Msi2 mRNA expression, and negatively correlated with Bax, C/EBP , RUNX3 and TIMP3 mRNA expression.Conclusion:The high expression of PRPS1 and JAB1 in the bone marrow tissue of acute leukemia can inhibit cell apoptosis and promote cell invasion.
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.
