title: 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.
authors.affiliation: Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.|Murdoch Children's Research Institute and Children's Cancer Centre, The Royal Children's Hospital, Parkville, VIC, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Narayan
authors.affiliation: Murdoch Children's Research Institute and Children's Cancer Centre, The Royal Children's Hospital, Parkville, VIC, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Morenos
authors.affiliation: Murdoch Children's Research Institute and Children's Cancer Centre, The Royal Children's Hospital, Parkville, VIC, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Phipson
authors.affiliation: Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.|Walter and Eliza Hall Institute, Parkville, VIC, Australia.
authors.forename: S N
authors.initials: SN
authors.lastname: Willis
authors.affiliation: Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Brumatti
authors.affiliation: Murdoch Children's Research Institute and Children's Cancer Centre, The Royal Children's Hospital, Parkville, VIC, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Eggers
authors.affiliation: Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute, Parkville, VIC, Australia.|Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Lalaoui
authors.affiliation: Murdoch Children's Research Institute and Children's Cancer Centre, The Royal Children's Hospital, Parkville, VIC, Australia.|Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia.
authors.forename: L M
authors.initials: LM
authors.lastname: Brown
authors.affiliation: Murdoch Children's Research Institute and Children's Cancer Centre, The Royal Children's Hospital, Parkville, VIC, Australia.
authors.forename: H J
authors.initials: HJ
authors.lastname: Kosasih
authors.affiliation: Murdoch Children's Research Institute and Children's Cancer Centre, The Royal Children's Hospital, Parkville, VIC, Australia.
authors.forename: R C
authors.initials: RC
authors.lastname: Bartolo
authors.affiliation: Tumour Bank, Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, NSW, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Tumour Bank, Children's Cancer Research Unit, The Children's Hospital at Westmead, Westmead, NSW, Australia.|Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia.|Faculty of Information Technology, The University of Technology Sydney, Sydney, NSW, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Catchpoole
authors.affiliation: Murdoch Children's Research Institute and Children's Cancer Centre, The Royal Children's Hospital, Parkville, VIC, Australia.|Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Saffery
authors.affiliation: Murdoch Children's Research Institute and Children's Cancer Centre, The Royal Children's Hospital, Parkville, VIC, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Oshlack
authors.affiliation: Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.|Department of Medicine, University of Adelaide, Adelaide, SA, Australia.
authors.forename: G J
authors.initials: GJ
authors.lastname: Goodall
authors.affiliation: Murdoch Children's Research Institute and Children's Cancer Centre, The Royal Children's Hospital, Parkville, VIC, Australia.|Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia.
authors.forename: P G
authors.initials: PG
authors.lastname: Ekert
mesh_terms: D000293:Adolescent; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic; D006410:Hematopoiesis / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D011379:Prognosis; D034622:RNA Interference; D014410:Tumor Stem Cell Assay
chemical_list: C490669:HOXB8 protein, human; D018398:Homeodomain Proteins; C524942:MIRN155 microRNA, human; D035683:MicroRNAs