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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)3726-3736
Number of pages11
JournalBlood
Volume115
Issue number18
DOIs
Publication statusPublished - May 6 2010

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Immunology
  • Hematology

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    Capitani, N., Lucherini, O. M., Sozzi, E., Ferro, M., Giommoni, N., Finetti, F., De Falco, G., Cencini, E., Raspadori, D., Pelicci, P. G., Lauria, F., Forconi, F., & Baldari, C. T. (2010). Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia. Blood, 115(18), 3726-3736. https://doi.org/10.1182/blood-2009-08-239244