Stams Wendy A G, den Boer Monique L, Beverloo H Berna, Meijerink Jules P P, Stigter Rolinda L, van Wering Elisabeth R, Janka-Schaub Gritta E, Slater Rosalyn, Pieters Rob
Erasmus MC/University Medical Center Rotterdam/Sophia Children's Hospital, Division of Pediatric Oncology/Hematology, Rotterdam, The Netherlands.
Blood. 2003 Apr 1;101(7):2743-7. doi: 10.1182/blood-2002-08-2446. Epub 2002 Nov 14.
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.
导致TEL/AML1基因融合的（12；21）易位存在于约25%的儿童前体B系急性淋巴细胞白血病（ALL）中，与良好的预后以及对L-天冬酰胺酶（L-Asp）的高细胞敏感性相关。由于天冬酰胺合成酶（AS）水平较低，ALL细胞被认为对L-Asp敏感。对L-Asp的耐药可能是由于细胞内AS水平升高，或者是耐药细胞在接触L-Asp后迅速诱导AS基因表达的能力所致。AS可能是受t（12；21）调控的一个靶点。我们研究了t（12；21）与AS的mRNA水平之间的关系，以探讨L-Asp敏感性潜在的机制。实时定量逆转录-聚合酶链反应（RT-PCR）分析令人惊讶地发现，30例t（12；21）阳性患者的AS mRNA表达量比17例t（12；21）阴性患者（P = 0.008）以及11份健康对照样本（P = 0.016）高5倍。t（12；21）（-）ALL与健康对照之间的AS mRNA水平没有差异。在体外接触L-Asp后，t（12；21）阳性或阴性的ALL患者上调AS的能力没有差异，排除了t（12；21）细胞在接触L-Asp后上调AS的能力存在缺陷。此外，未观察到AS mRNA表达与对L-Asp的敏感性之间存在相关性。我们得出结论，t（12；21）（+）儿童ALL对L-Asp的敏感性与AS基因的表达水平无关。此外，我们反驳了白血病细胞与正常骨髓和血细胞相比特异性缺乏AS的普遍观点。
