ADAMTSL5 and CDH11: putative epigenetic markers for therapeutic resistance in acute lymphoblastic leukemia
ADAMTSL5 and CDH11: putative epigenetic markers for therapeutic resistance in acute lymphoblastic leukemia
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DOI：
10.1080/10245332.2017.1299417
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发表时间：
2017-01-01
期刊：
影响因子：
1.9
通讯作者：
Hussin, Noor Hamidah
中科院分区：
文献类型：
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作者：
Abdullah, Maha;Choo, Chee Wei;Hussin, Noor Hamidah
背景和目标：DNA 高甲基化与儿童急性淋巴细胞白血病 (ALL) 治疗效果不佳有关。与化疗耐药性前 B-ALL 病例相比，化学反应性前 B-ALL 病例中差异甲基化的基因提供了潜在的预后标记。方法：在 27 000 个 CpG 位点微阵列芯片上比较了 5 名在诱导治疗后达到形态学完全缓解（化学反应性）的 B-ALL 儿童患者和 5 名未达到形态学完全缓解（化疗耐药性）的 B-ALL 患者以及 4 名正常对照的 DNA 甲基化谱。随后，对另外 37 个化疗反应性和 9 个化疗耐药性 B-ALL 样本以及 2 个正常对照进行选定的高甲基化基因的甲基化特异性聚合酶链反应 (MSP)。 结果：发现两种方法高度相关。无监督的主成分分析表明，化疗反应性和耐药性 B-ALL 患者可以彼此分离。以高严格性选择分离的基因，鉴定出两个潜在基因（CDH11 和 ADAMTSL5）。对较大样本组（42 个化疗敏感样本、14 个化疗耐药 B-ALL 样本和 6 个正常对照）的 MSP 分析显示，化疗耐药样本中 ADAMTSL5（93% vs. 38%；p = 0.0001）和 CDH11（79% vs. 40%，p < 0.01）的高甲基化率显着较高。所有对照病例均未甲基化。结论：化疗耐药的 B-ALL 患者与 ADAMTSL5 和 CDH11 甲基化增加相关。这些发现需要在更大的患者群体中进行验证，并且需要进一步研究差异甲基化的功能生物学和预后意义。
Background and objectives: DNA hypermethylation has been linked to poor treatment outcome in childhood acute lymphoblastic leukemia (ALL). Genes differentially methylated in the chemoresponsive pre-B-ALL compared to chemoresistant pre-B-ALL cases provide potential prognostic markers.Methods: DNA methylation profiles of five B-ALL childhood patients who achieved morphological complete remission (chemoresponsive) and five B-ALL patients who did not (chemoresistant) after induction treatments as well as four normal controls were compared on 27 000 CpG sites microarray chips. Subsequently, methylation-specific polymerase chain reaction (MSP) on selected hypermethylated genes was conducted on an additional 37 chemoresponsive and 9 chemoresistant B-ALL samples and 2 normal controls.Results: Both methods were found to be highly correlated. Unsupervised principal component analysis showed that the chemotherapy-responsive and - resistant B-ALL patients could be segregated from one another. Selection of segregated genes at high stringency identified two potential genes (CDH11 and ADAMTSL5). MSP analysis on the larger cohort of samples (42 chemoresponsive, 14 chemoresistant B-ALL samples and 6 normal controls) revealed significantly higher rates of hypermethylation in chemoresistant samples for ADAMTSL5 (93 vs. 38%; p = 0.0001) and CDH11 (79% vs. 40%, p < 0.01). All control cases remained unmethylated.Conclusion: Chemoresistant B-ALL patients are associated with increased methylation in ADAMTSL5 and CDH11. These findings need to be validated in a larger group of patients, and the functional biological and prognostic significance of differential methylation needs to be studied further.