Increase of PRPP enhances chemosensitivity of PRPS1 mutant acute lymphoblastic leukemia cells to 5‐Fluorouracil

Dan Wang,Yan Xu,Lijuan Du,Yao Chen,Hui Li,Bin‐Bing S Zhou,Fan Yang,Houshun Fang,Liang Zheng,Ying Li

doi:10.1111/jcmm.13907

Abstract

Relapse‐specific mutations in phosphoribosyl pyrophosphate synthetase 1 (PRPS1), a rate‐limiting purine biosynthesis enzyme, confer significant drug resistances to combination chemotherapy in acute lymphoblastic leukemia (ALL). It is of particular interest to identify drugs to overcome these resistances. In this study, we found that PRPS1 mutant ALL cells specifically showed more chemosensitivity to 5‐Fluorouracil (5‐FU) than control cells, attributed to increased apoptosis of PRPS1 mutant cells by 5‐FU. Mechanistically, PRPS1 mutants increase the level of intracellular phosphoribosyl pyrophosphate (PRPP), which causes the apt conversion of 5‐FU to FUMP and FUTP in Reh cells, to promote 5‐FU‐induced DNA damage and apoptosis. Our study not only provides mechanistic rationale for re‐targeting drug resistant cells in ALL, but also implicates that ALL patients who harbor relapse‐specific mutations of PRPS1 might benefit from 5‐FU‐based chemotherapy in clinical settings.

Highlights

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, accounting for more than 25% of all childhood cancers.[1]
We showed that knocking down pyrophosphate synthetase 1 gene (PRPS1) resulted in impaired conversion of 5‐FU to FUMP and fluorouridine triphosphate (FUTP) in Reh cells (Figure 5I and J), and a significant resistance of Reh cells to 5‐FU (Figure 5K), indicating that PRPP reduction can reduce the sensitivity of Reh cells to 5‐FU
Recent studies showed that expression level of PRPS1 is critical for tumorigenesis and clinical prognosis of cancer patients, based on the findings that both mRNA level and protein level of PRPS1 are up‐regulated in human colorectal cancer samples, and patients with high PRPS1 expression show poor prognosis.[19]

Summary

| INTRODUCTION

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, accounting for more than 25% of all childhood cancers.[1] risk‐stratified combination chemotherapy has improved the cure rate of ALL patients, relapsed ALL remains a leading cause of mortality among all childhood malignancies.[2] The thiopurines 6‐thioguanine (6‐TG) and 6‐mercaptopurine (6‐MP) are key drugs in maintenance therapy which will continue for the two to two‐and‐ a‐half years after initial remission, and both are prodrugs converted by the purine salvage pathway to cytotoxic thioguanine nucleotides.[3] dysfunction of the enzymes involved in purine metabolism has been associated with the ALL recurrence.[4] We previously identified multiple relapse‐specific mutations in phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes a rate‐limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapsed childhood B‐ALL samples. Our findings would bridge between PRPS1 mutant‐induced metabolic abnormality and prodrug activation of 5‐FU, suggesting a potential therapeutic strategy for drug resistant ALL patients with relapse‐specific PRPS1 mutations

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION