Differential regulation of hypoxia-induced CXCR4 triggering during B-cell development and lymphomagenesis.
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.
Piovan
Erich
E
Oncology Section, Department of Oncology and Surgical Sciences, University of Padova, Italy.
Tosello
Valeria
V
Indraccolo
Stefano
S
Masiero
Massimo
M
Persano
Luca
L
Esposito
Giovanni
G
Zamarchi
Rita
R
Ponzoni
Maurilio
M
Chieco-Bianchi
Luigi
L
Dalla-Favera
Riccardo
R
Amadori
Alberto
A
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
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