Blood, 1 June 2006, Vol. 107, No. 11, pp. 4244-4249.
Prepublished online as a Blood First Edition Paper on February 23, 2006; DOI 10.1182/blood-2005-06-2597.
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CLINICAL TRIALS AND OBSERVATIONS
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, and
Rob Pieters
From the Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children`s Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands; and the Dutch Childhood Oncology Group, The Hague, The Netherlands.
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/m2 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.
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