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.

*Drug Resistance, Neoplasm, *Gene Expression Regulation, Neoplastic, Asparaginase/*therapeutic use, Aspartate-Ammonia Ligase/analysis/*genetics, Child, Core Binding Factor Alpha 2 Subunit, Disease-Free Survival, Humans, Leukemia, B-Cell, Acute/drug therapy/mortality, Leukemia, Lymphocytic, Acute/drug therapy/*mortality, Oligonucleotide Array Sequence Analysis, Oncogene Proteins, Fusion/analysis, Prognosis, Recurrence, Research Support, Non-U.S. Gov't
Erasmus MC: University Medical Center Rotterdam

Stams, W.A, den Boer, M.L, Holleman, A, Appel, I.M, Beverloo, H.B, van Wering, E.R, … Pieters, R. (2005). Asparagine synthetase expression is linked with L-asparaginase resistance in TEL-AML1-negative but not TEL-AML1-positive pediatric acute lymphoblastic leukemia. Blood. Retrieved from