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Acute myeloid leukemia

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

Abstract

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.

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Acknowledgements

We thank the staff at WEHI Bioservices (Crystal Stivala, Nicole Lynch, Julie Merryfull and Jessica Mansheim) for assistance with animal work; the staff at WEHI Flow Facility for assistance with FACS sorting; Dr Francoise Mechinaud (Head of Oncology, Royal Children's Hospital), Dr Ngaire Elwood (Cord blood bank, MCRI), Dr Nick Wong (MCRI), Minhee Halemba (MCRI) and Jane Ng (MCRI) for procurement and preparation of paediatric samples. Grants from the Leukaemia Foundation (Australia), the National Health and Medical Research (NHMRC) Project grant, the Victorian Cancer Agency, My Room and the Children’s Cancer Centre Foundation supported paediatric AML work. We thank the Children’s Cancer Centre Tissue Bank (MCRI, The Royal Children’s Hospital) for supplying tumour samples and coded data, which is funded through generous support by CIKA (Cancer In Kids @ RCH), Leukaemia Auxiliary at RCH, MCRI and the Royal Children’s Hospital. We also thank Aedan Roberts and Aysen Yuksel for sample preparation at the Tumour Bank at the Children's Hospital at Westmead, which is generously supported by The Kids Cancer Project. We are greatful to Dr Johannes Zuber (The Research Institute of Molecular Pathology, Austria) for MYB and KIT shRNAs and Drs Mark McKenzie (WEHI), Luisa Cimmino (NYU School of Medicine, New York) and Ross Dickins (Monash University) for PU.1 shRNAs. We thank Andrew Bert (SA Pathology, Australia) for valuable technical expertise. Paul G Ekert is supported by the Children’s Cancer Foundation and the Steven Walter Children’s Cancer Foundation. Nisha Narayan was supported by the Australian Postgraduate Award PhD scholarship (University of Melbourne).

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Narayan, N., Morenos, L., Phipson, B. et al. Functionally distinct roles for different miR-155 expression levels through contrasting effects on gene expression, in acute myeloid leukaemia. Leukemia 31, 808–820 (2017). https://doi.org/10.1038/leu.2016.279

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