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 Blood, 1 June 2005, Vol. 105, No. 11, pp. 4223-4225.
Prepublished online as a Blood First Edition Paper on February 17, 2005; DOI 10.1182/blood-2004-10-3892.

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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Brief report

Asparagine synthetase expression is linked with L-asparaginase resistance in TEL-AML1–negative but not TEL-AML1–positive pediatric acute lymphoblastic leukemia

Wendy A. G. Stams, Monique L. den Boer, Amy Holleman, Inge M. Appel, H. Berna Beverloo, Elisabeth R. van Wering, Gritta E. Janka-Schaub, William E. Evans, and Rob Pieters

From the Erasmus Medical Center (MC)/University Medical Center Rotterdam/Sophia Children's Hospital, Division of Pediatric Oncology/Hematology, Rotterdam, The Netherlands; Erasmus MC/University Medical Center Rotterdam, Department of Clinical Genetics, Rotterdam, The Netherlands; Dutch Childhood Oncology Group, The Hague, The Netherlands; Cooperative Acute Lymphoblastic Leukemia (COALL) Study Group, Hamburg, Germany; and St Jude Children's Research Hospital, Department of Pharmaceutical Sciences, Memphis, TN.

Resistance to L-asparaginase in leukemic cells may be caused by an elevated cellular expression of asparagine synthetase (AS). Previously, we reported that high AS expression did not correlate to L-asparaginase resistance in TEL-AML1–positive B-lineage acute lymphoblastic leukemia (ALL). In the present study we confirmed this finding in TEL-AML1–positive patients (n = 28) using microarrays. In contrast, 35 L-asparaginase–resistant TEL-AML1–negative B-lineage ALL patients had a significant 3.5-fold higher AS expression than 43 sensitive patients (P < .001). Using real-time quantitative polymerase chain reaction (RTQ-PCR), this finding was confirmed in an independent group of 39 TEL-AML1–negative B-lineage ALL patients (P = .03). High expression of AS was associated with poor prognosis (4-year probability of disease-free survival [pDFS] 58% ± 11%) compared with low expression (4-year pDFS 83% ± 7%; P = .009). We conclude that resistance to L-asparaginase and relapse risk are associated with high expression of AS in TEL-AML1–negative but not TEL-AML1–positive B-lineage ALL.


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