Increase of PRPP enhances chemosensitivity of PRPS 1 mutant acute lymphoblastic leukemia cells to 5‐Fluorouracil

Relapse‐specific mutations in phosphoribosyl pyrophosphate synthetase 1 ( PRPS 1 ), 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 PRPS 1 mutant ALL cells specifically showed more chemosensitivity to 5‐Fluorouracil (5‐ FU ) than control cells, attributed to increased apoptosis of PRPS 1 mutant cells by 5‐ FU . Mechanistically, PRPS 1 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 PRPS 1 might benefit from 5‐ FU ‐based chemotherapy in clinical settings.