Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC.
Blood. 2011 Nov 24;118(22):5883-90. doi: 10.1182/blood-2011-05-355560. Epub 2011 Oct 4.
Asparaginase is a standard and critical component in the therapy of childhood acute lymphoblastic leukemia. Asparagine synthetase (ASNS) and the basic region leucine zipper activating transcription factor 5 (ATF5) and arginosuccinate synthase 1 (ASS1) have been shown to mediate the antileukemic effect of asparaginase and to display variable expression between leukemia cells that are resistant and sensitive to treatment. Fourteen polymorphisms in the regulatory and coding regions of these genes were investigated for an association with acute lymphoblastic leukemia outcome. Lower event-free survival (EFS) was associated with ATF5 T1562C, tandem-repeat ASNS polymorphism, derived haplotype, and ASS1 G1343T and G34T substitutions (P ≤ .03). Associations were limited to patients who received Escherichia coli asparaginase. Variations that sustained correction for multiple testing (ATF5 T1562C, P = .005; ASNS tandem-repeat and related haplotype, P ≤ .01) were subsequently analyzed in the replication cohort. The E coli-dependent association of the ATF5 T1562 allele with reduced EFS was confirmed (P = .01). A gene-reporter assay showed that the haplotype tagged by T1562 had higher promoter activity (P ≤ .01). The remaining regulatory polymorphisms also appeared to affect ATF5 function; 2 additional high-activity haplotypes were identified (P ≤ .02) and were further corroborated by quantitative mRNA analysis in lymphoblastoid cell lines. The ATF5-regulated increase in ASNS expression in response to more efficacious E coli-induced asparagine depletion may explain our observed results.
天冬酰胺酶是儿童急性淋巴细胞白血病治疗的标准和关键组成部分。天冬酰胺合成酶（ASNS）和碱性区域亮氨酸拉链激活转录因子 5（ATF5）和精氨琥珀酸合成酶 1（ASS1）已被证明介导天冬酰胺酶的抗白血病作用，并在对治疗敏感和耐药的白血病细胞之间显示出可变表达。研究了这些基因的调节和编码区域中的 14 种多态性与急性淋巴细胞白血病结果的关联。较低的无事件生存（EFS）与 ATF5 T1562C、串联重复 ASNS 多态性、衍生单倍型和 ASS1 G1343T 和 G34T 取代有关（P ≤.03）。这些关联仅限于接受大肠埃希菌天冬酰胺酶治疗的患者。经过多次测试校正（ATF5 T1562C，P =.005；ASNS 串联重复和相关单倍型，P ≤.01）的变异随后在复制队列中进行了分析。证实了 ATF5 T1562 等位基因与降低 EFS 相关的 E coli 依赖性关联（P =.01）。基因报告基因测定表明，由 T1562 标记的单倍型具有更高的启动子活性（P ≤.01）。其余的调节多态性似乎也影响了 ATF5 功能；还确定了另外 2 个高活性单倍型（P ≤.02），并通过淋巴母细胞系的定量 mRNA 分析进一步证实。ATF5 调节的 ASNS 表达增加是对更有效的 E coli 诱导的天冬酰胺耗竭的反应，这可能解释了我们观察到的结果。
