Asparagine synthetase expression alone is sufficient to induce l-asparaginase resistance in MOLT-4 human leukaemia cells

Biochem J. 2001 Jul 1;357(Pt 1):321-8. doi: 10.1042/0264-6021:3570321.


Childhood acute lymphoblastic leukaemia (ALL) is treated by combination chemotherapy with a number of drugs, always including the enzyme L-asparaginase (ASNase). Although the initial remission rate is quite high, relapse and associated drug resistance are a significant problem. In vitro studies have demonstrated increased asparagine synthetase (AS) expression in ASNase-resistant cells, which has led to the hypothesis that elevated AS activity permits drug-resistant survival. The data presented show that not only is elevated AS expression a property of ASNase-resistant MOLT-4 human leukaemia cells, but that short-term (12 h) treatment of the cells with ASNase causes a relatively rapid induction of AS expression. The results also document that the elevated expression of AS in ASNase-resistant cells is not fully reversible, even 6 weeks after ASNase removal from the culture medium. Furthermore, ASNase resistance, assessed as both drug-insensitive cell growth rates and decreased drug-induced apoptosis, parallels this irreversible AS expression. Mimicking the elevated AS activity in ASNase-resistant cells by overexpression of the human AS protein by stable retroviral transformation of parental MOLT4 cells is sufficient to induce the ASNase-resistance phenotype. These data document that ASNase resistance in ALL cells is a consequence of elevated AS expression and that although other drug-induced metabolic changes occur, they are secondary to the increased asparagine biosynthetic rate.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects
  • Asparaginase / toxicity*
  • Aspartate-Ammonia Ligase / genetics*
  • Aspartate-Ammonia Ligase / metabolism*
  • Cell Division / drug effects
  • Cell Survival / drug effects
  • Clone Cells
  • Drug Resistance, Neoplasm*
  • Genetic Vectors
  • Humans
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Recombinant Proteins / metabolism
  • Transcription, Genetic*
  • Transfection
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • Recombinant Proteins
  • Asparaginase
  • Aspartate-Ammonia Ligase