Up-regulation of asparagine synthetase expression is not linked to the clinical response to L-asparaginase in pediatric acute lymphoblastic leukemia
Up-regulation of asparagine synthetase expression is not linked to the clinical response to L-asparaginase in pediatric acute lymphoblastic leukemia
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DOI：
10.1182/blood-2005-06-2597
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发表时间：
2006-06-01
期刊：
影响因子：
20.3
通讯作者：
Pieters, Rob
中科院分区：
文献类型：
--
作者：
Appel, Inge M.;den Boer, Monique L.;Pieters, Rob
左旋门冬酰胺酶（L-Asp）是治疗儿童急性淋巴细胞白血病（ALL）的有效药物。一般认为，有效性是由于血清和细胞中天冬酰胺的快速消耗。天冬酰胺合成酶（AS）通过天冬酰胺的再合成来对抗L-天冬氨酸的作用。在体外，对L-Asp的抗性与AS mRNA表达的上调相关。我们监测了初诊ALL患儿在治疗窗内静脉注射1000 IU/m2聚乙二醇化L-天冬酰胺酶（PEG-Asp）之前和之后5天内白血病细胞中AS mRNA的水平。在24小时内，AS mRNA水平增加了3.5倍，并在随后的4天内保持稳定。基线和L-Asp诱导的AS表达水平在PEG-Asp临床良好、中度和不良应答者之间无差异。前体B-和T-ALL之间、超二倍体、TEL/AML 1重排和无遗传异常的ALL之间AS mRNA的表达无显著差异。在12例T-ALL患者中，有3例在L-Asp暴露后AS mRNA表达轻微下调。总之，尽管L-Asp暴露诱导AS mRNA表达，但上调的基因表达与ALL儿童对该药物的早期临床不良反应无关。
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.