Enforced expression of miR-155 in myeloid cells has been shown to have both oncogenic or tumour suppressor functions in acute myeloid leukemia (AML). We sought to resolve these contrasting effects of miR-155 overexpression using murine models of AML and human paediatric AML datasets. 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, favors 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 hematopoiesis and leukemia. Furthermore, we show that elevated miR-155 expression detected in pediatric 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.Leukemia accepted article preview online, 14 October 2016. doi:10.1038/leu.2016.279.
Cell Signalling and Cell Death; Molecular Immunology