title: Vitamin D Receptor Expression in Plasmablastic Lymphoma and Myeloma Cells Confers Susceptibility to Vitamin D.
abstract: Plasmablastic B-cell malignancies include plasmablastic lymphoma and subsets of multiple myeloma and diffuse large B-cell lymphomaDLBCL. These diseases can be difficult to diagnose and treat, and they lack well-characterized cell line models. Here, immunophenotyping and FOXP1 expression profiling identified plasmablastic characteristics in DLBCL cell lines HLY-1 and SU-DHL-9, associated with CTNNAL1, HPGD, RORA, IGF1, and/or vitamin D receptor (VDR) transcription. We demonstrated VDR protein expression in primary plasmablastic tumor cells and confirmed in cell lines expression of both VDR and the metabolic enzyme CYP27B1, which catalyzes active vitamin D3 production. Although Vdr and Cyp27b1 transcription in normal B cells were activated by interleukin 4 (IL-4) and CD40 signaling, respectively, unstimulated malignant plasmablastic cells lacking IL-4 expressed both VDR and CYP27B1. Positive autoregulation evidenced intact VDR function in all plasmablastic lines, and inhibition of growth by active vitamin D3 was both dependent on MYC protein inhibition and could be enhanced by cotreatment with a synthetic ROR ligand SR-1078. Furthermore, a VDR polymorphism, FOK1, was associated with greater vitamin D3-dependent growth inhibition. In summary, HLY-1 provides an important model of strongly plasmablastic lymphoma, and disruption of VDR pathway activity may be of therapeutic benefit in both plasmablastic lymphoma and myeloma.
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford , Oxford , UK.
authors.forename: Duncan M
authors.initials: DM
authors.lastname: Gascoyne
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford , Oxford , UK.
authors.forename: Linden
authors.initials: L
authors.lastname: Lyne
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford , Oxford , UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Spearman
authors.affiliation: Department of Oncology, University of Oxford, United Kingdom.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford , Oxford , UK.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Soilleux
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford , Oxford , UK.
authors.forename: Alison H
authors.initials: AH
authors.lastname: Banham
mesh_terms: D000818:Animals; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000069293:Plasmablastic Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D005466:Fluorocarbons
chemical_list: D001549:Benzamides; D002762:Cholecalciferol; D051858:Forkhead Transcription Factors; D018167:Receptors, Calcitriol; D012097:Repressor Proteins; C432917:Foxp1 protein, mouse; C559087:SR 1078; D005466:Fluorocarbons