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Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia

Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia
Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia
Intrinsic apoptosis defects underlie to a large extent the extended survival of malignant B cells in chronic lymphocytic leukemia (CLL). Here, we show that the Shc family adapter p66Shc uncouples the B-cell receptor (BCR) from the Erk- and Akt-dependent survival pathways, thereby enhancing B-cell apoptosis. p66Shc expression was found to be profoundly impaired in CLL B cells compared with normal peripheral B cells. Moreover, significant differences in p66Shc expression were observed in patients with favorable or unfavorable prognosis, based on the mutational status of IGHV genes, with the lowest expression in the unfavorable prognosis group. Analysis of the expression of genes implicated in apoptosis defects of CLL showed an alteration in the balance of proapoptotic and antiapoptotic members of the Bcl-2 family in patients with CLL. Reconstitution experiments in CLL B cells, together with data obtained on B cells from p66Shc(-/-) mice, showed that p66Shc expression correlates with a bias in the Bcl-2 family toward proapoptotic members. The data identify p66Shc as a novel regulator of B-cell apoptosis which attenuates BCR-dependent survival signals and modulates Bcl-2 family expression. They moreover provide evidence that the p66Shc expression defect in CLL B cells may be causal to the imbalance toward the antiapoptotic Bcl-2 family members in these cells.
0006-4971
3726-3736
Capitani, Nagaja
4dd8f26a-f593-460e-ab3f-84470b922549
Lucherini, Orso Maria
d808d274-4e5d-4011-931f-5faf3cc718a0
Sozzi, Elisa
e811ff23-6fe9-47ec-b052-fe8d34d1e36b
Ferro, Micol
75cbf300-d9e3-473a-b9b0-bdc5f94660f3
Giommoni, Nico
01589520-7fd7-468e-a02d-8bf19199344c
Finetti, Francesca
0057fcc5-4970-420a-8e17-bac3e04ed62b
De Falco, Giulia
03ab3028-5691-4b9c-9392-9a7987300630
Cencini, Emanuele
3dc5d188-96b0-4f7d-abb8-af4d22638d7e
Raspadori, Donatella
185f6866-6d10-4f86-9add-72938cea80b3
Pelicci, Pier Giuseppe
e3049658-83e3-4054-a20d-9a9cce3f439f
Lauria, Francesco
f01f163b-abcb-4aad-b952-f4356692f519
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Baldari, Cosima T.
cd28b84c-46b3-43e4-863b-cb47a9475b4c
Capitani, Nagaja
4dd8f26a-f593-460e-ab3f-84470b922549
Lucherini, Orso Maria
d808d274-4e5d-4011-931f-5faf3cc718a0
Sozzi, Elisa
e811ff23-6fe9-47ec-b052-fe8d34d1e36b
Ferro, Micol
75cbf300-d9e3-473a-b9b0-bdc5f94660f3
Giommoni, Nico
01589520-7fd7-468e-a02d-8bf19199344c
Finetti, Francesca
0057fcc5-4970-420a-8e17-bac3e04ed62b
De Falco, Giulia
03ab3028-5691-4b9c-9392-9a7987300630
Cencini, Emanuele
3dc5d188-96b0-4f7d-abb8-af4d22638d7e
Raspadori, Donatella
185f6866-6d10-4f86-9add-72938cea80b3
Pelicci, Pier Giuseppe
e3049658-83e3-4054-a20d-9a9cce3f439f
Lauria, Francesco
f01f163b-abcb-4aad-b952-f4356692f519
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Baldari, Cosima T.
cd28b84c-46b3-43e4-863b-cb47a9475b4c

Capitani, Nagaja, Lucherini, Orso Maria, Sozzi, Elisa, Ferro, Micol, Giommoni, Nico, Finetti, Francesca, De Falco, Giulia, Cencini, Emanuele, Raspadori, Donatella, Pelicci, Pier Giuseppe, Lauria, Francesco, Forconi, Francesco and Baldari, Cosima T. (2010) Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia. Blood, 115 (18), 3726-3736. (doi:10.1182/blood-2009-08-239244). (PMID:20061561)

Record type: Article

Abstract

Intrinsic apoptosis defects underlie to a large extent the extended survival of malignant B cells in chronic lymphocytic leukemia (CLL). Here, we show that the Shc family adapter p66Shc uncouples the B-cell receptor (BCR) from the Erk- and Akt-dependent survival pathways, thereby enhancing B-cell apoptosis. p66Shc expression was found to be profoundly impaired in CLL B cells compared with normal peripheral B cells. Moreover, significant differences in p66Shc expression were observed in patients with favorable or unfavorable prognosis, based on the mutational status of IGHV genes, with the lowest expression in the unfavorable prognosis group. Analysis of the expression of genes implicated in apoptosis defects of CLL showed an alteration in the balance of proapoptotic and antiapoptotic members of the Bcl-2 family in patients with CLL. Reconstitution experiments in CLL B cells, together with data obtained on B cells from p66Shc(-/-) mice, showed that p66Shc expression correlates with a bias in the Bcl-2 family toward proapoptotic members. The data identify p66Shc as a novel regulator of B-cell apoptosis which attenuates BCR-dependent survival signals and modulates Bcl-2 family expression. They moreover provide evidence that the p66Shc expression defect in CLL B cells may be causal to the imbalance toward the antiapoptotic Bcl-2 family members in these cells.

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e-pub ahead of print date: 8 January 2010
Published date: 6 May 2010
Organisations: Cancer Sciences

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Local EPrints ID: 341166
URI: https://eprints.soton.ac.uk/id/eprint/341166
ISSN: 0006-4971
PURE UUID: 2a384d1d-97a7-49ba-91e3-86b599797b3c

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Date deposited: 17 Jul 2012 08:54
Last modified: 16 Jul 2019 21:58

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Contributors

Author: Nagaja Capitani
Author: Orso Maria Lucherini
Author: Elisa Sozzi
Author: Micol Ferro
Author: Nico Giommoni
Author: Francesca Finetti
Author: Giulia De Falco
Author: Emanuele Cencini
Author: Donatella Raspadori
Author: Pier Giuseppe Pelicci
Author: Francesco Lauria
Author: Cosima T. Baldari

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