Involvement of miR17 pathway in glucocorticoid-induced cell death in pediatric acute lymphoblastic leukemia
Involvement of miR17 pathway in glucocorticoid-induced cell death in pediatric acute lymphoblastic leukemia
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DOI：
10.3109/10428194.2012.678004
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发表时间：
2012-10-01
影响因子：
2.6
通讯作者：
Corcoran, Martin
中科院分区：
文献类型：
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作者：
Harada, Masako;Pokrovskaja-Tamm, Katja;Corcoran, Martin
对地塞米松处理急性淋巴细胞白血病(ALL)细胞系RS4；11后的microRNA转录组的分析显示，microRNA水平在全球范围内下调。染色质免疫沉淀(ChIP)分析显示，MIR17HG在治疗后迅速下调，该启动子是糖皮质激素(GC)转录抑制的直接靶点，miR17-92簇是地塞米松诱导的抑制的主要靶点。在另外一个ALL细胞系SUP-B15中，miR17家族表达的缺失和miR17靶基因BIM的伴随增加发生在地塞米松耐药的REH中。通过上调或抑制miR17水平的改变分别导致Bim蛋白水平降低和地塞米松诱导的细胞死亡增加。原代体外地塞米松诱导的ALL细胞也下调miR17水平。因此，miR17的下调在糖皮质激素诱导的细胞死亡中起着重要作用，提示靶向miR17可能会改善目前的ALL联合治疗。
Analysis of the microRNA transcriptome following dexamethasone treatment of the acute lymphocytic leukemia (ALL) cell line RS4;11 showed a global down-regulation of microRNA levels. MIR17HG was rapidly down-regulated following treatment, with chromatin immunoprecipitation (ChIP) analysis demonstrating the promoter to be a direct target of glucocorticoid (GC)-transcriptional repression and revealing the miR17-92 cluster as a prime target for dexamethasone-induced repression. The loss of miR17 family expression and concomitant increases in the miR17 target Bim occurred in an additional ALL cell line SUP-B15 but not in the dexamethasone-resistant REH. Alteration of miR17 levels through up-regulation or inhibition resulted in an decrease and increase, respectively, in Bim protein levels and dexamethasone-induced cell death. Primary ex vivo ALL cells that underwent apoptosis induced by dexamethasone also down-regulated miR17 levels. Thus, down-regulation of miR17 plays an important role in glucocorticoid-induced cell death suggesting that targeting miR17 may improve the current ALL combination therapy.