1. Functionally distinct roles for different miR-155 expression levels through contrasting effects on gene expression, in acute myeloid leukaemia
- Author
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Alicia Oshlack, Belinda Phipson, Lauren M Brown, L Morenos, Hansen J. Kosasih, Stefanie Eggers, Simon N. Willis, Paul G Ekert, L Zhou, Gregory J. Goodall, Gabriela Brumatti, Ray C Bartolo, N Narayan, Richard Saffery, Najoua Lalaoui, Daniel Catchpoole, 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, and Ekert, PG
- Subjects
0301 basic medicine ,Cancer Research ,Myeloid ,Adolescent ,microRNA-155 ,Gene Expression ,Kaplan-Meier Estimate ,Biology ,miR-155 ,Mice ,03 medical and health sciences ,RNA interference ,Cell Line, Tumor ,hemic and lymphatic diseases ,microRNA ,Gene expression ,medicine ,Animals ,Humans ,acute myeloid leukaemia ,Child ,Tumor Stem Cell Assay ,Cell Proliferation ,Homeodomain Proteins ,Regulation of gene expression ,Gene Expression Regulation, Leukemic ,Infant, Newborn ,Infant ,Hematology ,Prognosis ,medicine.disease ,Hematopoiesis ,Disease Models, Animal ,Leukemia, Myeloid, Acute ,MicroRNAs ,Haematopoiesis ,Leukemia ,Cell Transformation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Child, Preschool ,myeloid cells ,Cancer research ,RNA Interference - 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. Refereed/Peer-reviewed
- Published
- 2017