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Functionally distinct roles foar different miR-155 expression levels through contrasting effects on gene expression, in acute myeloid leukemia


Narayan, N; Morenos, L; Phipson, B; Willis, SN; Brumatti, G; Eggers, S; Lalaoui, N; Brown, LM; Kosasih, HJ; Bartolo, RC; Zhou, L; Catchpoole, D; Saffery, R; Oshlack, A; Goodall, GJ; Ekert, PG
2017-04
2016-10-14
Leukemia
Journal Article
31
4
808-820
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.
Springer Nature
Cell Signalling and Cell Death; Molecular Immunology
10.1038/leu.2016.279
27740637
Refer to copyright notice on published article.

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Creation Date 2016-10-19 11:52:31 Last Modified 2018-07-05 03:45:05