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

S1P1 expression is controlled by the pro-oxidant activity of p66Shc and is impaired in B-CLL patients with unfavorable prognosis
S1P1 expression is controlled by the pro-oxidant activity of p66Shc and is impaired in B-CLL patients with unfavorable prognosis
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.
0006-4971
4391-4399
Capitani, Nagaja
4dd8f26a-f593-460e-ab3f-84470b922549
Patrussi, Laura
ed68e393-8a95-4f3e-afc7-7bdbf68208e5
Trentin, Livio
457595df-2d40-4392-931c-3919eb5620ec
Lucherini, Orso Maria
d808d274-4e5d-4011-931f-5faf3cc718a0
Cannizzaro, Enrica
9c45097a-9591-4822-a4fa-b2a641160931
Migliaccio, Enrica
8f03f693-8a11-4c53-baf0-0f4b3ffd9a14
Frezzato, Federica
be67ae36-4e66-48aa-b198-f548f80ade1b
Gattazzo, Cristina
b8fbfcc1-8a8e-4602-8435-1e50fa3110f1
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Pelicci, Piergiuseppe
d8be8257-b3d8-48a1-8c86-84dbb288b9c5
Semenzato, Gianpietro
a6d11836-d0b3-4e68-b8ed-2aba2ea18b4f
Baldari, Cosima T.
cd28b84c-46b3-43e4-863b-cb47a9475b4c
Capitani, Nagaja
4dd8f26a-f593-460e-ab3f-84470b922549
Patrussi, Laura
ed68e393-8a95-4f3e-afc7-7bdbf68208e5
Trentin, Livio
457595df-2d40-4392-931c-3919eb5620ec
Lucherini, Orso Maria
d808d274-4e5d-4011-931f-5faf3cc718a0
Cannizzaro, Enrica
9c45097a-9591-4822-a4fa-b2a641160931
Migliaccio, Enrica
8f03f693-8a11-4c53-baf0-0f4b3ffd9a14
Frezzato, Federica
be67ae36-4e66-48aa-b198-f548f80ade1b
Gattazzo, Cristina
b8fbfcc1-8a8e-4602-8435-1e50fa3110f1
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Pelicci, Piergiuseppe
d8be8257-b3d8-48a1-8c86-84dbb288b9c5
Semenzato, Gianpietro
a6d11836-d0b3-4e68-b8ed-2aba2ea18b4f
Baldari, Cosima T.
cd28b84c-46b3-43e4-863b-cb47a9475b4c

Capitani, Nagaja, Patrussi, Laura, Trentin, Livio, Lucherini, Orso Maria, Cannizzaro, Enrica, Migliaccio, Enrica, Frezzato, Federica, Gattazzo, Cristina, Forconi, Francesco, Pelicci, Piergiuseppe, Semenzato, Gianpietro and Baldari, Cosima 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. (doi:10.1182/blood-2012-04-425959). (PMID:23033271)

Record type: Article

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.

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e-pub ahead of print date: 1 October 2012
Published date: 22 November 2012
Organisations: Cancer Sciences

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Local EPrints ID: 358106
URI: https://eprints.soton.ac.uk/id/eprint/358106
ISSN: 0006-4971
PURE UUID: be5e126f-9f31-47e3-9e0d-5b05b01126ed

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Date deposited: 04 Oct 2013 10:05
Last modified: 16 Jul 2019 21:21

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Contributors

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

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