title: Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia.
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.
authors.affiliation: Department of Evolutionary Biology, University of Siena, 53100 Siena, Italy.
authors.forename: Nagaja
authors.initials: N
authors.lastname: Capitani
authors.forename: Orso Maria
authors.initials: OM
authors.lastname: Lucherini
authors.forename: Elisa
authors.initials: E
authors.lastname: Sozzi
authors.forename: Micol
authors.initials: M
authors.lastname: Ferro
authors.forename: Nico
authors.initials: N
authors.lastname: Giommoni
authors.forename: Francesca
authors.initials: F
authors.lastname: Finetti
authors.forename: Giulia
authors.initials: G
authors.lastname: De Falco
authors.forename: Emanuele
authors.initials: E
authors.lastname: Cencini
authors.forename: Donatella
authors.initials: D
authors.lastname: Raspadori
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.forename: Francesco
authors.initials: F
authors.lastname: Lauria
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.forename: Cosima T
authors.initials: CT
authors.lastname: Baldari
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism*; D015153:Blotting, Western; D016022:Case-Control Studies; D002470:Cell Survival; D019175:DNA Methylation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C496613:BCR protein, human; D051057:Proto-Oncogene Proteins c-akt; D051562:Proto-Oncogene Proteins c-bcr; D048049:Extracellular Signal-Regulated MAP Kinases