title: Differential regulation of hypoxia-induced CXCR4 triggering during B-cell development and lymphomagenesis.
abstract: The chemokine receptor CXCR4 plays a central role in organ-specific homing and tumor spreading and is induced by hypoxia. B lymphocytes are exposed to low oxygen tensions during their development, but the influence of hypoxia on their physiology is poorly understood. Here, we show that hypoxia is associated with up-regulation of CXCR4 expression in human normal and malignant B cells, through both transcriptional and posttranslational mechanisms. However, a dichotomic functional response to CXCR4 triggering was observed: both peripheral B cells and lymphomas arising from mature B cells displayed increased responses to CXCR4 triggering under hypoxia, whereas germinal center (GC) B cells as well as GC-derived lymphomas showed CXCR4 receptor desensitization. This phenomenon was associated with differential modulation of key signal-transducing molecules, including mitogen-activated protein kinase phosphatase-1 and regulator of G protein signaling molecule-1. The unresponsiveness of GC-derived lymphomatous B cells to CXCR4 triggering under hypoxia may have implications for the development and pathogenesis of GC-derived lymphoid tumors.
authors: Oncology Section, Department of Oncology and Surgical Sciences, University of Padova, Italy.
authors: Erich
authors: E
authors: Piovan
authors: Valeria
authors: V
authors: Tosello
authors: Stefano
authors: S
authors: Indraccolo
authors: Massimo
authors: M
authors: Masiero
authors: Luca
authors: L
authors: Persano
authors: Giovanni
authors: G
authors: Esposito
authors: Rita
authors: R
authors: Zamarchi
authors: Maurilio
authors: M
authors: Ponzoni
authors: Luigi
authors: L
authors: Chieco-Bianchi
authors: Riccardo
authors: R
authors: Dalla-Favera
authors: Alberto
authors: A
authors: Amadori
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology / Q000502:physiology*; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D020710:RGS Proteins / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020710:RGS Proteins; C080831:RGS1 protein, human; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1