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

• DOI: 10.1111/jcmm.13907
• Publication Date: 2018-09-26T06:28:28Z
• Authors: Dan Wang; Yao Chen; Houshun Fang; Liang Zheng; Ying Li; Fan Yang; Yan Xu; Lijuan Du; Bin‐Bing S. Zhou; Hui Li
• Keywords: 0301 basic medicine; Cell Survival; Gene Expression Regulation, Leukemic; Lentivirus; Apoptosis; Phosphoribosyl Pyrophosphate; Original Articles; Precursor Cell Lymphoblastic Leukemia-Lymphoma; 3. Good health; Jurkat Cells; Mice; 03 medical and health sciences; Ribose-Phosphate Pyrophosphokinase; Animals; Heterografts; Humans; Fluorouracil; DNA Damage

AbstractRelapse‐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.