Glucocorticoid-regulated microRNAs and mirtrons in acute lymphoblastic leukemia
Glucocorticoid-regulated microRNAs and mirtrons in acute lymphoblastic leukemia
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DOI：
10.1038/leu.2008.370
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发表时间：
2009-04-01
期刊：
影响因子：
11.4
通讯作者：
Kofler, R.
中科院分区：
文献类型：
--
作者：
Rainer, J.;Ploner, C.;Kofler, R.
糖皮质激素(GCs)可诱导淋巴系细胞的凋亡，因此被用于急性淋巴细胞白血病(ALL)及相关恶性肿瘤的治疗。MicroRNAs(MiRNAs)及其相关的Mirtrans类似于22个核苷酸RNAs，来源于聚合酶-II转录本，参与调控基本的生物学功能，包括细胞凋亡。GCs是否调节编码miRNA的转录单位尚不清楚。我们研究了8个白血病/淋巴瘤体外模型和13个接受全身GC单一治疗的ALL儿童的miRNA/mirtron的表达和GC调节，采用表达谱技术、实时逆转录(RT)-PCR和Northern blotting相结合的方法检测成熟的miRNA和/或其前体。我们发现，成熟的miRNA调控可以从其宿主基因的表达数据中推断出来。尽管没有出现一条简单的miRNA启动的经典途径来诱导GC诱导的细胞凋亡或细胞周期停滞，但我们在患者和细胞系中发现了几个受GC调控的miRNAs/Mirtron，包括髓系特异的miR-223和类似于16个簇的诱导凋亡和细胞周期停滞的miR15。在体外模型中，类似于16个模拟物的miR15b的过度表达增加，而类似于16个抑制剂的miR15b的沉默降低了GC的敏感性。因此，在GC治疗过程中观察到的miRNA/mirtron表达的复杂变化可能有助于以细胞上下文依赖的方式发挥抗白血病GC效应。
Glucocorticoids (GCs) induce apoptosis in lymphoid lineage cells and are therefore used in the therapy of acute lymphoblastic leukemia (ALL) and related malignancies. MicroRNAs (miRNAs) and the related mirtrons are similar to 22 nucleotide RNAs derived from polymerase-II transcripts and implicated in the control of essential biological functions, including apoptosis. Whether GCs regulate miRNA-encoding transcription units is unknown. We investigated miRNA/mirtron expression and GC regulation in 8 leukemia/lymphoma in vitro models and 13 ALL children undergoing systemic GC monotherapy using a combination of expression profiling techniques, real time reverse transcription (RT)-PCR and northern blotting to detect mature miRNAs and/or their precursors. We found that mature miRNA regulations can be inferred from expression data of their host genes. Although a simple miRNA-initiated canonical pathway to GC-induced apoptosis or cell cycle arrest did not emerge, we identified several miRNAs/mirtrons that were regulated by GC in patients and cell lines, including the myeloid-specific miR-223 and the apoptosis and cell cycle arrest-inducing miR15 similar to 16 clusters. In an in vitro model, overexpression of miR15b similar to 16 mimics increased and silencing by miR15b similar to 16 inhibitors decreased GC sensitivity. Thus, the observed complex changes in miRNA/mirtron expression during GC treatment might contribute to the anti-leukemic GC effects in a cell context-dependent manner.