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

J Cell Mol Med. 2018 Dec;22(12):6202-6212. doi: 10.1111/jcmm.13907. Epub 2018 Sep 25.

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.

Keywords: 5-FU; PRPP; PRPS1; acute lymphoblastic leukemia; nucleotide metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Survival / drug effects
  • DNA Damage / drug effects
  • Fluorouracil / pharmacology*
  • Gene Expression Regulation, Leukemic / drug effects
  • Heterografts
  • Humans
  • Jurkat Cells
  • Lentivirus / genetics
  • Mice
  • Phosphoribosyl Pyrophosphate / genetics
  • Phosphoribosyl Pyrophosphate / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Ribose-Phosphate Pyrophosphokinase / genetics*

Substances

  • Phosphoribosyl Pyrophosphate
  • PRPS1 protein, human
  • Ribose-Phosphate Pyrophosphokinase
  • Fluorouracil