A genome-wide view of the in vitro response to l-asparaginase in acute lymphoblastic leukemia.
A genome-wide view of the in vitro response to l-asparaginase in acute lymphoblastic leukemia.
复制标题
DOI：
10.1158/0008-5472.291.65.1
复制
发表时间：
2005-01
期刊：
影响因子：
11.2
通讯作者：
B. Fine;G. Kaspers;M. Ho;A. Loonen;L. Boxer
中科院分区：
文献类型：
--
作者：
B. Fine;G. Kaspers;M. Ho;A. Loonen;L. Boxer
为了探讨L-天冬酰胺酶在急性淋巴细胞白血病(ALL)中的作用，我们利用基因芯片技术获得了L-天冬酰胺酶在细胞株和儿童ALL标本中基线和体外作用后基因表达的全基因组图。在16个细胞系中，一个基线基因表达模式区分了L-天冬酰胺酶敏感和耐药。然而，在28个儿童ALL样本中，没有一致的基线表达模式与L-天冬酰胺酶的敏感性相关。特别是，天冬酰胺合成酶的基线表达并不能预测对L-天冬酰胺酶的反应。经L-天冬酰胺酶作用后，5个细胞株和10个临床标本显示出非常相似的大量基因表达的变化。然而，在临床样本中，基因表达的变化发生得较慢。这些变化包括tRNA合成酶和溶质转运体的表达持续增加，激活转录因子和CCAAT/增强子结合蛋白家族成员，这与氨基酸饥饿时观察到的反应相似。许多与增殖相关的基因也持续减少。综上所述，这些变化似乎反映了细胞系和临床样本对天冬酰胺饥饿的一致协调反应。重要的是，在临床标本中，L-天冬酰胺酶暴露后ASNS的表达增加与体外对L-天冬酰胺酶耐药无关，这表明体外L-天冬酰胺酶耐药的ASNS非依赖性机制在ALL中普遍存在。这些结果表明，靶向所有细胞中参与氨基酸饥饿反应的特定基因可能为克服L天冬酰胺酶抗性提供一种新的方法。
To investigate the effect of l-asparaginase on acute lymphoblastic leukemia (ALL), we used cDNA microarrays to obtain a genome-wide view of gene expression both at baseline and after in vitro exposure to l-asparaginase in cell lines and pediatric ALL samples. In 16 cell lines, a baseline gene expression pattern distinguished l-asparaginase sensitivity from resistance. However, for 28 pediatric ALL samples, no consistent baseline expression pattern was associated with sensitivity to l-asparaginase. In particular, baseline expression of asparagine synthetase (ASNS) was not predictive of response to l-asparaginase. After exposure to l-asparaginase, 5 cell lines and 10 clinical samples exhibited very similar changes in the expression of a large number of genes. However, the gene expression changes occurred more slowly in the clinical samples. These changes included a consistent increase in expression of tRNA synthetases and solute transporters and activating transcription factor and CCAAT/enhancer binding protein family members, a response similar to that observed with amino acid starvation. There was also a consistent decrease in many genes associated with proliferation. Taken together, the changes seem to reflect a consistent coordinated response to asparagine starvation in both cell lines and clinical samples. Importantly, in the clinical samples, increased expression of ASNS after l-asparaginase exposure was not associated with in vitro resistance to l-asparaginase, indicating that ASNS-independent mechanisms of in vitro l-asparaginase resistance are common in ALL. These results suggest that targeting particular genes involved in the response to amino acid starvation in ALL cells may provide a novel way to overcome l-asparaginase resistance.