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

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dc.contributor.authorNarayan, N.
dc.contributor.authorMorenos, L.
dc.contributor.authorPhipson, B.
dc.contributor.authorWillis, S.
dc.contributor.authorBrumatti, G.
dc.contributor.authorEggers, S.
dc.contributor.authorLalaoui, N.
dc.contributor.authorBrown, L.
dc.contributor.authorKosasih, H.
dc.contributor.authorBartolo, R.
dc.contributor.authorZhou, L.
dc.contributor.authorCatchpoole, D.
dc.contributor.authorSaffery, R.
dc.contributor.authorOshlack, A.
dc.contributor.authorGoodall, G.
dc.contributor.authorEkert, P.
dc.date.issued2017
dc.description.abstractEnforced 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.Leukemia advance online publication, 18 November 2016; doi:10.1038/leu.2016.279.
dc.description.statementofresponsibilityN. Narayan, L. Morenos, B. Phipson, S. N. Willis, G. Brumatti, S. Eggers, N. Lalaoui, L. M. Brown, H. J. Kosasih, R. C. Bartolo, L. Zhou, D. Catchpoole, R. Saffery, A. Oshlack, G. J. Goodall and P. G. Ekert
dc.identifier.citationLeukemia, 2017; 31(4):808-820
dc.identifier.doi10.1038/leu.2016.279
dc.identifier.issn0887-6924
dc.identifier.issn1476-5551
dc.identifier.orcidGoodall, G. [0000-0003-1294-0692]
dc.identifier.urihttp://hdl.handle.net/2440/118197
dc.language.isoen
dc.publisherSpringer Nature
dc.rights© 2016, Springer Nature
dc.source.urihttps://doi.org/10.1038/leu.2016.279
dc.subjectAcute myeloid leukaemia; cancer genetics; cell biology; gene expression; miRNAs
dc.titleFunctionally distinct roles for different miR-155 expression levels through contrasting effects on gene expression, in acute myeloid leukaemia
dc.typeJournal article
pubs.publication-statusPublished

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