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

被引:64
作者
Appel, Inge M.
den Boer, Monique L.
Meijerink, Jules P. P.
Veerman, Anjo J. P.
Reniers, Nathalie C. M.
Pieters, Rob
机构
[1] Erasmus Univ, Med Ctr, Sophia Childrens Hosp, Dept Pediat Oncol Hematol, NL-3000 CB Rotterdam, Netherlands
[2] Dutch Childhood Oncol Grp, The Hague, Netherlands
关键词
D O I
10.1182/blood-2005-06-2597
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 upregulation 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.
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收藏
页码:4244 / 4249
页数:6
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