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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)4244-9
Aantal pagina's6
TijdschriftBlood
Volume107
Nummer van het tijdschrift11
DOI's
StatusGepubliceerd - 1 jun. 2006
Extern gepubliceerdJa

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