title: Allelic mutations in noncoding genomic sequences construct novel transcription factor binding sites that promote gene overexpression.
abstract: The growth and survival factor hepatocyte growth factor (HGF) is expressed at high levels in multiple myeloma (MM) cells. We report here that elevated HGF transcription in MM was traced to DNA mutations in the promoter alleles of HGF. Sequence analysis revealed a previously undiscovered single-nucleotide polymorphism (SNP) and crucial single-nucleotide variants (SNVs) in the promoters of myeloma cells that produce large amounts of HGF. The allele-specific mutations functionally reassembled wild-type sequences into the motifs that affiliate with endogenous transcription factors NFKB (nuclear factor kappa-B), MZF1 (myeloid zinc finger 1), and NRF-2 (nuclear factor erythroid 2-related factor 2). In vitro, a mutant allele that gained novel NFKB-binding sites directly responded to transcriptional signaling induced by tumor necrosis factor alpha (TNFα) to promote high levels of luciferase reporter. Given the recent discovery by genome-wide sequencing (GWS) of numerous non-coding mutations in myeloma genomes, our data provide evidence that heterogeneous SNVs in the gene regulatory regions may frequently transform wild-type alleles into novel transcription factor binding properties to aberrantly interact with dysregulated transcriptional signals in MM and other cancer cells.
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.|The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR.
authors.forename: Erming
authors.initials: E
authors.lastname: Tian
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Immunology and Transfusion Medicine, St. Olavs Hospital, Trondheim, Norway.
authors.forename: Magne
authors.initials: M
authors.lastname: Børset
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Sawyer
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Gaute
authors.initials: G
authors.lastname: Brede
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Thea K
authors.initials: TK
authors.lastname: Våtsveen
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Håkon
authors.initials: H
authors.lastname: Hov
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Waage
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR.
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.affiliation: Signal Genetics Inc., Carlsbad, CA.
authors.forename: John D
authors.initials: JD
authors.lastname: Shaughnessy
authors.affiliation: The Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR.
authors.forename: Joshua
authors.initials: J
authors.lastname: Epstein
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Sundan
mesh_terms: D000483:Alleles; D001665:Binding Sites; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C066855:HGF protein, human; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor