S1P1 expression is controlled by the pro-oxidant activity of p66Shc and is impaired in B-CLL patients with unfavorable prognosis

Nagaja Capitani, Laura Patrussi, Livio Trentin, Orso Maria Lucherini, Enrica Cannizzaro, Enrica Migliaccio, Federica Frezzato, Cristina Gattazzo, Francesco Forconi, Piergiuseppe Pelicci, Gianpietro Semenzato, Cosima T. Baldari

Research output: Contribution to journalArticle

Abstract

Although intrinsic apoptosis defects are causal to the extended survival of chronic lymphocytic leukemia (CLL) B cells, several lines of evidence support a contribution of the peripheral lymphoid organs and BM microenvironment to the extended lifespan of leukemic B cells. Lymphocyte trafficking is controlled by homing signals provided by stromal cell-derived chemokines and egress signals provided by sphingosine-1-phosphate (S1P). In the present study, we show that expression of S1P1, the S1P receptor responsible for lymphocyte egress, is selectively reduced in CLL B cells with unmutated IGHV. Expression of S1P2, which controls B-cell homeostasis, is also impaired in CLL B cells but independently of the IGHV mutational status.We provide evidence herein that p66Shc, a Shc adaptor family member the deficiency of which is implicated in the apoptosis defects of CLL B cells, controls S1P1 expression through its pro-oxidant activity. p66Shc also controls the expression of the homing receptor CCR7, which opposes S1P1 by promoting lymphocyte retention in peripheral lymphoid organs. The results of the present study provide insights into the regulation of S1P1 expression in B cells and suggest that defective egress caused by impaired S1P1 expression contributes to the extended survival of CLL B cells by prolonging their residency in the prosurvival niche of peripheral lymphoid organs.

Original languageEnglish
Pages (from-to)4391-4399
Number of pages9
JournalBlood
Volume120
Issue number22
DOIs
Publication statusPublished - Nov 22 2012

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Capitani, N., Patrussi, L., Trentin, L., Lucherini, O. M., Cannizzaro, E., Migliaccio, E., Frezzato, F., Gattazzo, C., Forconi, F., Pelicci, P., Semenzato, G., & Baldari, C. T. (2012). S1P1 expression is controlled by the pro-oxidant activity of p66Shc and is impaired in B-CLL patients with unfavorable prognosis. Blood, 120(22), 4391-4399. https://doi.org/10.1182/blood-2012-04-425959