title: The Leukemia Inhibitory Factor Receptor Gene Is a Direct Target of RUNX1.
abstract: Activation of cytokine signaling via the leukemia inhibitory factor receptor (LIFR) plays an integral role in hematopoiesis, osteogenesis, and placental development, along with mediating neurotrophic mechanisms. However, the regulatory control of the LIFR gene has remained largely unexplored. Here, we characterize the LIFR gene as a novel target of the RUNX1 transcription factor. The RUNX1 transcription factor is an essential regulator of hematopoiesis and is a frequent target of point mutations and chromosomal alterations in leukemia. RUNX1 regulates hematopoiesis through its control of genes important for hematopoietic cell growth, proliferation, and differentiation, including a number of cytokines and cytokine receptors. LIFR is regulated by two alternate promoters: a placental-specific and a ubiquitously active general promoter. We show that both of these promoters are regulated by RUNX1. However, in myeloid cells LIFR expression is driven solely by the general LIFR promoter with our data indicating that the placental promoter is epigenetically silenced in these cells. While RUNX1 activates the LIFR general promoter, the oncogenic RUNX1-ETO fusion protein generated by the t(8;21) translocation commonly associated with acute myeloid leukemia represses promoter activity. The data presented here establish LIFR as a transcriptional target of RUNX1 and suggest that disruption of RUNX1 activity in myeloid cells may result in altered LIFR signaling in these cells.
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia.
authors.forename: Abeer A
authors.initials: AA
authors.lastname: Qadi
authors.affiliation: Genomics and Epigenetics Division, The Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Phillippa C
authors.initials: PC
authors.lastname: Taberlay
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Phillips
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia.
authors.forename: Arabella
authors.initials: A
authors.lastname: Young
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia.
authors.forename: Alison C
authors.initials: AC
authors.lastname: West
authors.affiliation: School of Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia.
authors.forename: Kate H
authors.initials: KH
authors.lastname: Brettingham-Moore
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia.
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Dickinson
authors.affiliation: School of Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia.
authors.forename: Adele F
authors.initials: AF
authors.lastname: Holloway
mesh_terms: D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D002869:Chromosome Aberrations; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D022423:Myeloid Cells / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D053606:Receptors, OSM-LIF / Q000235:genetics / Q000378:metabolism*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C493728:RUNX1 protein, human; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF
keywords: GENE REGULATION; LIFR; RUNX1