PRPS2 mutations drive acute lymphoblastic leukemia relapse through influencing PRPS1/2 hexamer stability

Area of Science:

• Biochemistry
• Oncology
• Genetics

Background:

• Tumor relapse is a primary cause of treatment failure in childhood acute lymphoblastic leukemia (ALL).
• The molecular mechanisms underlying ALL relapse remain largely unknown.
• Thiopurine therapy is a common treatment for ALL, but resistance can develop.

Purpose of the Study:

• To investigate the role of phosphoribosyl pyrophosphate synthetase 2 (PRPS2) mutations in childhood ALL relapse.
• To elucidate the functional impact of PRPS2 mutations on purine metabolism and thiopurine resistance.
• To identify PRPS2 mutations as potential biomarkers for relapsed ALL.

Main Methods:

• Ultra-deep sequencing of PRPS2 in ALL samples.
• Functional assays evaluating cell survival, apoptosis, and drug resistance.
• In vitro enzyme activity assays and feedback inhibition studies.
• Analysis of purine metabolites using UPLC-MS/MS.
• Xenograft models to assess thiopurine resistance.

Main Results:

• PRPS2 mutations were identified exclusively in relapsed childhood ALL patients treated with thiopurines.
• Mutant PRPS2 altered purine metabolism, reduced nucleotide feedback inhibition, and enhanced thiopurine resistance.
• Specific PRPS2 mutations (e.g., V103-G104-E105 insertion, P173R) impaired enzyme activity and increased drug resistance.
• PRPS2 P173R mutation conferred thiopurine resistance in xenograft models.

Conclusions:

• PRPS2 mutations represent a novel mechanism driving childhood ALL relapse.
• Altered PRPS2 function mediates resistance to thiopurine therapy.
• PRPS2 mutations serve as promising biomarkers for identifying and potentially targeting relapsed childhood ALL.