Up-regulation of asparagine synthetase expression is not linked to the clinical response L-asparaginase in pediatric acute lymphoblastic leukemia

Inge M Appel, Monique L den Boer, Jules P P Meijerink, Anjo J P Veerman, Nathalie C M Reniers, Rob Pieters

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)

Abstract

L-asparaginase (L-Asp) is an effective drug for treatment of children with acute lymphoblastic leukemia (ALL). The effectiveness is generally thought to result from a rapid depletion of asparagine in serum and cells. Asparagine synthetase (AS) opposes the action of L-Asp by resynthesis of asparagine. In vitro, resistance to L-Asp has been associated with up-regulation of AS mRNA expression. We monitored AS mRNA levels in leukemic cells before and during 5 days after intravenous administration of 1000 IU/m(2) pegylated L-asparaginase (PEG-Asp) in a therapeutic window in children with ALL at initial diagnosis. Within 24 hours, AS mRNA levels increased by 3.5-fold and remained stable in the following 4 days. Baseline and L-Asp-induced expression levels of AS did not differ between clinically good, intermediate, and poor responders to PEG-Asp. No significant difference of AS mRNA up-regulation was found between precursor B- and T-ALL or between hyperdiploids, TEL/AML1 rearranged ALL or absence of genetic abnormalities. In 3 of 12 patients with T-ALL even a slight down-regulation of AS mRNA expression upon L-Asp exposure was found. In conclusion, although L-Asp exposure induces the expression of AS mRNA, the up-regulated gene expression does not correlate with an early clinical poor response to this drug in children with ALL.

Original languageEnglish
Pages (from-to)4244-9
Number of pages6
JournalBlood
Volume107
Issue number11
DOIs
Publication statusPublished - 1 Jun 2006
Externally publishedYes

Keywords

  • Adolescent
  • Antineoplastic Agents/pharmacology
  • Asparaginase/pharmacology
  • Aspartate-Ammonia Ligase/genetics
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Infant
  • Leukemia-Lymphoma, Adult T-Cell/drug therapy
  • Male
  • Polyethylene Glycols/pharmacology
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
  • RNA, Neoplasm/analysis
  • Treatment Outcome
  • Up-Regulation/drug effects

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