title: Sensitivity to L-asparaginase is not associated with expression levels of asparagine synthetase in t(12;21)+ pediatric ALL.
abstract: The (12;21) translocation resulting in TEL/AML1 gene fusion is present in about 25% of childhood precursor B-lineage acute lymphoblastic leukemia (ALL) and is associated with a good prognosis and a high cellular sensitivity to L-asparaginase (L-Asp). ALL cells are thought to be sensitive to L-Asp due to lower asparagine synthetase (AS) levels. Resistance to L-Asp may be caused by an elevated cellular level of AS or by the ability of resistant cells to rapidly induce the expression of the AS gene on L-Asp exposure. AS may be a target regulated by t(12;21). We studied the relationship between t(12;21) and the mRNA level of AS to investigate a possible mechanism underlying L-Asp sensitivity. Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis surprisingly revealed that 30 patients positive for t(12;21) expressed 5-fold more AS mRNA compared with 17 patients negative for t(12;21) (P =.008) and 11 samples from healthy controls (P =.016). The mRNA levels of AS between t(12;21)(-) ALL and healthy controls did not differ. No difference was found between ALL patients positive or negative for t(12;21) in the capacity to up-regulate AS after in vitro L-Asp exposure, excluding a defective capacity for t(12;21) cells in up-regulating AS on L-Asp exposure. Moreover, no correlation was observed between AS mRNA expression and sensitivity to L-Asp. We conclude that the sensitivity of t(12;21)(+) childhood ALL to L-Asp is not associated with the expression level of the AS gene. Furthermore, we contradict the general thought that leukemic cells specifically lack AS compared with normal bone marrow and blood cells.
authors.affiliation: Erasmus MC/University Medical Center Rotterdam/Sophia Children's Hospital, Division of Pediatric Oncology/Hematology, Rotterdam, The Netherlands. stams@kgk.fgg.eur.nl
authors.forename: Wendy A G
authors.initials: WA
authors.lastname: Stams
authors.forename: Monique L
authors.initials: ML
authors.lastname: den Boer
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.forename: Jules P P
authors.initials: JP
authors.lastname: Meijerink
authors.forename: Rolinda L
authors.initials: RL
authors.lastname: Stigter
authors.forename: Elisabeth R
authors.initials: ER
authors.lastname: van Wering
authors.forename: Gritta E
authors.initials: GE
authors.lastname: Janka-Schaub
authors.forename: Rosalyn
authors.initials: R
authors.lastname: Slater
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
mesh_terms: D001215:Asparaginase / Q000494:pharmacology* / Q000627:therapeutic use; D001217:Aspartate-Ammonia Ligase / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002881:Chromosomes, Human, Pair 12; D002891:Chromosomes, Human, Pair 21; D006801:Humans; D007223:Infant; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D014178:Translocation, Genetic; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D012333:RNA, Messenger; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase