Differential regulation of hypoxia-induced CXCR4 triggering during B-cell development and lymphomagenesis

Erich Piovan, Valeria Tosello, Stefano Indraccolo, Massimo Masiero, Luca Persano, Giovanni Esposito, Rita Zamarchi, Maurilio Ponzoni, Luigi Chieco-Bianchi, Riccardo Dalla-Favera, Alberto Amadori

Research output: Contribution to journalArticle

26 Citations (Scopus)

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, where as 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.

Original languageEnglish
Pages (from-to)8605-8614
Number of pages10
JournalCancer Research
Volume67
Issue number18
DOIs
Publication statusPublished - Sep 15 2007

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Germinal Center
B-Lymphocytes
Mitogen-Activated Protein Kinase Phosphatases
Dual Specificity Phosphatase 1
GTP-Binding Protein Regulators
CXCR4 Receptors
Chemokine Receptors
B-Cell Lymphoma
Lymphoma
Neoplasms
Up-Regulation
Hypoxia
Oxygen

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Differential regulation of hypoxia-induced CXCR4 triggering during B-cell development and lymphomagenesis. / Piovan, Erich; Tosello, Valeria; Indraccolo, Stefano; Masiero, Massimo; Persano, Luca; Esposito, Giovanni; Zamarchi, Rita; Ponzoni, Maurilio; Chieco-Bianchi, Luigi; Dalla-Favera, Riccardo; Amadori, Alberto.

In: Cancer Research, Vol. 67, No. 18, 15.09.2007, p. 8605-8614.

Research output: Contribution to journalArticle

Piovan, Erich ; Tosello, Valeria ; Indraccolo, Stefano ; Masiero, Massimo ; Persano, Luca ; Esposito, Giovanni ; Zamarchi, Rita ; Ponzoni, Maurilio ; Chieco-Bianchi, Luigi ; Dalla-Favera, Riccardo ; Amadori, Alberto. / Differential regulation of hypoxia-induced CXCR4 triggering during B-cell development and lymphomagenesis. In: Cancer Research. 2007 ; Vol. 67, No. 18. pp. 8605-8614.
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AU - Persano, Luca

AU - Esposito, Giovanni

AU - Zamarchi, Rita

AU - Ponzoni, Maurilio

AU - Chieco-Bianchi, Luigi

AU - Dalla-Favera, Riccardo

AU - Amadori, Alberto

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AB - 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, where as 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.

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