Asparagine synthetase expression is linked with L-asparaginase resistance in TEL-AML1-negative but not TEL-AML1-positive pediatric acute lymphoblastic leukemia.
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.
Stams
Wendy A G
WA
Erasmus Medical Ceneter/University Medical Center Rotterdam/Sophia Children's Hospital, Division of Pediatric Oncology/Hematology, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands.
den Boer
Monique L
ML
Holleman
Amy
A
Appel
Inge M
IM
Beverloo
H Berna
HB
van Wering
Elisabeth R
ER
Janka-Schaub
Gritta E
GE
Evans
William E
WE
Pieters
Rob
R
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
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