Journal
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
Volume 22, Issue 12, Pages 6202-6212Publisher
WILEY
DOI: 10.1111/jcmm.13907
Keywords
5-FU; acute lymphoblastic leukemia; nucleotide metabolism; PRPP; PRPS1
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Funding
- National Natural Science Foundation of China [31530017, 81500112]
- Rising-Star Program from the Science and Technology Commission of Shanghai Municipality
- Outstanding Youth of Shanghai Municipal Commission of Health and Family Planning
- Science and Technology Commission of Pudong New Area Foundation
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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.
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