Faculty of Life Sciences, The University of Manchester, Manchester, UK.
Oncogene. 2013 Jun 20;32(25):3039-48. doi: 10.1038/onc.2012.321. Epub 2012 Aug 6.
Glucocorticoids (GCs) are among the most widely prescribed medications in clinical practice. The beneficial effects of GCs in acute lymphoblastic leukemia (ALL) are based on their ability to induce apoptosis, but the underlying transcriptional mechanisms remain poorly defined. Computational modeling has enormous potential in the understanding of biological processes such as apoptosis and the discovery of novel regulatory mechanisms. We here present an integrated analysis of gene expression kinetic profiles using microarrays from GC sensitive and resistant ALL cell lines and patients, including newly generated and previously published data sets available from the Gene Expression Omnibus. By applying time-series clustering analysis in the sensitive ALL CEM-C7-14 cells, we identified 358 differentially regulated genes that we classified into 15 kinetic profiles. We identified GC response element (GRE) sequences in 33 of the upregulated known or potential GC receptor (GR) targets. Comparative study of sensitive and resistant ALL showed distinct gene expression patterns and indicated unexpected similarities between sensitivity-restored and resistant ALL. We found that activator protein 1 (AP-1), Ets related gene (Erg) and GR pathways were differentially regulated in sensitive and resistant ALL. Erg protein levels were substantially higher in CEM-C1-15-resistant cells, c-Jun was significantly induced in sensitive cells, whereas c-Fos was expressed at low levels in both. c-Jun was recruited on the AP-1 site on the Bim promoter, whereas a transient Erg occupancy on the GR promoter was detected. Inhibition of Erg and activation of GR lead to increased apoptosis in both sensitive and resistant ALL. These novel findings significantly advance our understanding of GC sensitivity and can be used to improve therapy of leukemia.
糖皮质激素（GCs）是临床实践中应用最广泛的药物之一。GC 在急性淋巴细胞白血病（ALL）中的有益作用基于其诱导细胞凋亡的能力，但潜在的转录机制仍未明确。计算模型在理解细胞凋亡等生物学过程和发现新的调控机制方面具有巨大的潜力。我们在此对使用来自 GC 敏感和耐药 ALL 细胞系和患者的微阵列进行基因表达动力学分析进行了综合分析，包括从基因表达综合数据库（GEO）中获取的新生成和先前发表的数据。通过对敏感 ALL CEM-C7-14 细胞中的时间序列聚类分析，我们鉴定了 358 个差异调节基因，将其分为 15 个动力学图谱。我们在 33 个上调的已知或潜在 GC 受体（GR）靶标中鉴定了 GC 反应元件（GRE）序列。敏感和耐药 ALL 的比较研究显示出不同的基因表达模式，并表明敏感性恢复和耐药 ALL 之间存在意外的相似性。我们发现，激活蛋白 1（AP-1）、Ets 相关基因（Erg）和 GR 途径在敏感和耐药 ALL 中存在差异调节。在 CEM-C1-15 耐药细胞中，erg 蛋白水平显著升高，在敏感细胞中 c-Jun 显著诱导，而 c-Fos 在两者中表达水平均较低。c-Jun 被募集到 Bim 启动子上的 AP-1 位点，而在 GR 启动子上检测到 Erg 的瞬时占据。erg 的抑制和 GR 的激活导致敏感和耐药 ALL 中细胞凋亡增加。这些新发现显著提高了我们对 GC 敏感性的理解，并可用于改善白血病的治疗。
