title: Alternative RUNX1 Promoter Regulation by Wnt/β-Catenin Signaling in Leukemia Cells and Human Hematopoietic Progenitors.
abstract: Two distantly located promoter regions regulate the dynamic expression of RUNX genes during development: distal P1 and proximal P2 promoters. We have recently described that β-catenin increases total Runx1 mRNA levels in human CD34(+) hematopoietic progenitors and enhances spatial proximity with its translocation partner ETO. Here, we report that induction of Wnt/β-catenin signaling in HL60 and Jurkat leukemia-derived cell lines and CD34(+) progenitors selectively activate the production of the longer distal P1-Runx1 mRNA isoform. Gain- and loss-of-function experiments revealed that the differential increase in P1-Runx1 expression is accomplished through a minimal β-catenin responsive region that includes a highly conserved TCF/LEF-binding element, located -20/-16 bp upstream of the canonical distal P1-Runx1 transcription start site. We conclude that the distal P1-Runx1 promoter is a direct transcriptional target of Wnt/β-catenin signaling that may be important in normal hematopoiesis or its transition into malignant stem cells during the onset or progression of leukemia.
authors.affiliation: Faculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research, Universidad Andres Bello, Santiago, Chile.
authors.forename: Matías A
authors.initials: MA
authors.lastname: Medina
authors.affiliation: Faculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research, Universidad Andres Bello, Santiago, Chile.
authors.forename: Giorgia D
authors.initials: GD
authors.lastname: Ugarte
authors.affiliation: Faculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research, Universidad Andres Bello, Santiago, Chile.
authors.forename: Macarena F
authors.initials: MF
authors.lastname: Vargas
authors.affiliation: Faculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research, Universidad Andres Bello, Santiago, Chile.
authors.forename: Miguel E
authors.initials: ME
authors.lastname: Avila
authors.affiliation: Faculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research, Universidad Andres Bello, Santiago, Chile.
authors.forename: David
authors.initials: D
authors.lastname: Necuñir
authors.affiliation: Faculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research, Universidad Andres Bello, Santiago, Chile.|Millennium Institute on Immunology and Immunotherapy, Santiago, Chile.
authors.forename: Alvaro A
authors.initials: AA
authors.lastname: Elorza
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Universidad de Concepción, Concepción, Chile.
authors.forename: Soraya E
authors.initials: SE
authors.lastname: Gutiérrez
authors.affiliation: Faculty of Biological Sciences and Faculty of Medicine, Center for Biomedical Research, Universidad Andres Bello, Santiago, Chile.
authors.forename: Giancarlo V
authors.initials: GV
authors.lastname: De Ferrari
mesh_terms: D050676:Core Binding Factor Alpha 2 Subunit / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D014157:Transcription Factors; D051176:beta Catenin