title: Asparagine synthetase expression is linked with L-asparaginase resistance in TEL-AML1-negative but not TEL-AML1-positive pediatric acute lymphoblastic leukemia.
abstract: 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.
authors.affiliation: Erasmus Medical Ceneter/University Medical Center Rotterdam/Sophia Children's Hospital, Division of Pediatric Oncology/Hematology, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands.
authors.forename: Wendy A G
authors.initials: WA
authors.lastname: Stams
authors.forename: Monique L
authors.initials: ML
authors.lastname: den Boer
authors.forename: Amy
authors.initials: A
authors.lastname: Holleman
authors.forename: Inge M
authors.initials: IM
authors.lastname: Appel
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Elisabeth R
authors.initials: ER
authors.lastname: van Wering
authors.forename: Gritta E
authors.initials: GE
authors.lastname: Janka-Schaub
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
mesh_terms: D001215:Asparaginase / Q000627:therapeutic use*; D001217:Aspartate-Ammonia Ligase / Q000032:analysis / Q000235:genetics*; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000401:mortality; D002648:Child; D050676:Core Binding Factor Alpha 2 Subunit; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000032:analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000401:mortality*; D011379:Prognosis; D012008:Recurrence; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein