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Differential Regulation of Hypoxia-Induced CXCR4 Triggering during B-Cell Development and Lymphomagenesis

¹ Oncology Section, Department of Oncology and Surgical Sciences, University of Padova; ² Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Oncologico Veneto, Padua, Italy; ³ Institute for Cancer Genetics and the Departments of Pathology and Genetics and Development, Columbia University, New York, New York; and ⁴ Pathology Unit, San Raffaele Hospital Scientific Institute, Milan, Italy

Requests for reprints: Alberto Amadori, Department of Oncology and Surgical Sciences, Oncology Section, University of Padova, via Gattamelata 64, Padua I-35128, Italy. Phone: 39-049-8215891; Fax: 39-049-8072854; E-mail: albido{at}unipd.it.

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. [Cancer Res 2007;67(18):8605–14]

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