Functionally distinct roles for different miR-155 expression levels through contrasting effects on gene expression, in acute myeloid leukaemia
Functionally distinct roles for different miR-155 expression levels through contrasting effects on gene expression, in acute myeloid leukaemia
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DOI：
10.1038/leu.2016.279
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发表时间：
2017-04-01
期刊：
影响因子：
11.4
通讯作者：
Ekert, P. G.
中科院分区：
文献类型：
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作者：
Narayan, N.;Morenos, L.;Ekert, P. G.
髓系细胞中microRNA-155 （miR-155）的强制表达已被证明在急性髓系白血病（AML）中具有致癌或肿瘤抑制功能。我们试图通过小鼠AML模型和人类儿科AML数据集来解决miR-155过表达的这些对比效应。我们发现，在小鼠AML模型中，miR-155的最高表达水平抑制了增殖。然而，随着时间的推移，体外和体内AML中miR-155的强制表达有利于选择中间miR-155表达水平，从而导致小鼠肿瘤负荷增加，而不会加速疾病的发作。引人注目的是，我们发现miR-155的中高表达也调节着miR-155靶点的不同亚群，并对AML细胞的转录环境（包括参与造血和白血病的基因）具有不同的下游影响。此外，我们发现在儿科AML中检测到的miR-155表达升高与我们的实验模型中发现的中度和非高水平miR-155表达相关。这些发现共同描述了miR-155在AML调控中的一种新的剂量依赖性作用，这可能具有重要的治疗意义。
Enforced expression of microRNA-155 (miR-155) in myeloid cells has been shown to have both oncogenic or tumour-suppressor functions in acute myeloid leukaemia (AML). We sought to resolve these contrasting effects of miR-155 overexpression using murine models of AML and human paediatric AML data sets. We show that the highest miR-155 expression levels inhibited proliferation in murine AML models. Over time, enforced miR-155 expression in AML in vitro and in vivo, however, favours selection of intermediate miR-155 expression levels that results in increased tumour burden in mice, without accelerating the onset of disease. Strikingly, we show that intermediate and high miR-155 expression also regulate very different subsets of miR-155 targets and have contrasting downstream effects on the transcriptional environments of AML cells, including genes involved in haematopoiesis and leukaemia. Furthermore, we show that elevated miR-155 expression detected in paediatric AML correlates with intermediate and not high miR-155 expression identified in our experimental models. These findings collectively describe a novel dose-dependent role for miR-155 in the regulation of AML, which may have important therapeutic implications.