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 ap...
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| Veröffentlicht in: | Blood 2010-05, Vol.115 (18), p.3726-3736 |
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| creator | 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 Baldari, Cosima T. |
| description | 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. |
| doi_str_mv | 10.1182/blood-2009-08-239244 |
| format | Article |
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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.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2009-08-239244</identifier><identifier>PMID: 20061561</identifier><language>eng</language><publisher>Washington, DC: Elsevier Inc</publisher><subject>Animals ; Apoptosis ; B-Lymphocytes - metabolism ; Biological and medical sciences ; Blotting, Western ; Case-Control Studies ; Cell Survival ; DNA Methylation ; Extracellular Signal-Regulated MAP Kinases - genetics ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Hematologic and hematopoietic diseases ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell - genetics ; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism ; Leukemia, Lymphocytic, Chronic, B-Cell - pathology ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Medical sciences ; Mice ; Mice, Knockout ; Promoter Regions, Genetic - genetics ; Proto-Oncogene Proteins c-akt - genetics ; Proto-Oncogene Proteins c-akt - metabolism ; Proto-Oncogene Proteins c-bcl-2 - genetics ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Proto-Oncogene Proteins c-bcr - genetics ; Proto-Oncogene Proteins c-bcr - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Shc Signaling Adaptor Proteins - metabolism ; Signal Transduction ; Src Homology 2 Domain-Containing, Transforming Protein 1</subject><ispartof>Blood, 2010-05, Vol.115 (18), p.3726-3736</ispartof><rights>2010 American Society of Hematology</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-c9b64032c6ab25d8cca2f7c76cb56c367c943262c6332f8b36be04e8a6b741f73</citedby><cites>FETCH-LOGICAL-c391t-c9b64032c6ab25d8cca2f7c76cb56c367c943262c6332f8b36be04e8a6b741f73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22745827$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20061561$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Capitani, Nagaja</creatorcontrib><creatorcontrib>Lucherini, Orso Maria</creatorcontrib><creatorcontrib>Sozzi, Elisa</creatorcontrib><creatorcontrib>Ferro, Micol</creatorcontrib><creatorcontrib>Giommoni, Nico</creatorcontrib><creatorcontrib>Finetti, Francesca</creatorcontrib><creatorcontrib>De Falco, Giulia</creatorcontrib><creatorcontrib>Cencini, Emanuele</creatorcontrib><creatorcontrib>Raspadori, Donatella</creatorcontrib><creatorcontrib>Pelicci, Pier Giuseppe</creatorcontrib><creatorcontrib>Lauria, Francesco</creatorcontrib><creatorcontrib>Forconi, Francesco</creatorcontrib><creatorcontrib>Baldari, Cosima T.</creatorcontrib><title>Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia</title><title>Blood</title><addtitle>Blood</addtitle><description>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.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>B-Lymphocytes - metabolism</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Case-Control Studies</subject><subject>Cell Survival</subject><subject>DNA Methylation</subject><subject>Extracellular Signal-Regulated MAP Kinases - genetics</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - genetics</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</subject><subject>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Proto-Oncogene Proteins c-akt - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Proto-Oncogene Proteins c-bcl-2 - genetics</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Proto-Oncogene Proteins c-bcr - genetics</subject><subject>Proto-Oncogene Proteins c-bcr - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Shc Signaling Adaptor Proteins - metabolism</subject><subject>Signal Transduction</subject><subject>Src Homology 2 Domain-Containing, Transforming Protein 1</subject><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcuO1DAQRS0EYpqBP0DIG8RmDH7FcTZIw4jHSCOxANaWU6nQBicOdtKi_56EbmDHypbqXPvqFCFPBX8phJWv2phSxyTnDeOWSdVIre-RnaikZZxLfp_sOOeG6aYWF-RRKd84F1rJ6iG5WFNGVEbsSHc7TD5k7Cj-nDKWEtJIU08nYz7t4Yp6OqYDRprx6xL9nPI2fMMAY6RlyYdw8PGKhpHCPqcxAI3HYdonOM7bHZfvOAT_mDzofSz45Hxeki_v3n6--cDuPr6_vbm-Y6AaMTNoWqO5kmB8K6vOAnjZ11AbaCsDytTQrP3NOldK9rZVpkWu0XrT1lr0tbokL07vTjn9WLDMbghlq-pHTEtxtVJK8FraldQnEnIqJWPvphwGn49OcLfpdb_1uk2v49ad9K6xZ-cPlnbA7m_oj88VeH4GfAEf--xHCOUfJ2tdWbk1fX3icNVxCJhdgYAjYLfuAmbXpfD_Jr8AKp-Y5A</recordid><startdate>20100506</startdate><enddate>20100506</enddate><creator>Capitani, Nagaja</creator><creator>Lucherini, Orso Maria</creator><creator>Sozzi, Elisa</creator><creator>Ferro, Micol</creator><creator>Giommoni, Nico</creator><creator>Finetti, Francesca</creator><creator>De Falco, Giulia</creator><creator>Cencini, Emanuele</creator><creator>Raspadori, Donatella</creator><creator>Pelicci, Pier Giuseppe</creator><creator>Lauria, Francesco</creator><creator>Forconi, Francesco</creator><creator>Baldari, Cosima T.</creator><general>Elsevier Inc</general><general>Americain Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20100506</creationdate><title>Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia</title><author>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 ; Baldari, Cosima T.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c391t-c9b64032c6ab25d8cca2f7c76cb56c367c943262c6332f8b36be04e8a6b741f73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>B-Lymphocytes - metabolism</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Case-Control Studies</topic><topic>Cell Survival</topic><topic>DNA Methylation</topic><topic>Extracellular Signal-Regulated MAP Kinases - genetics</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - genetics</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - metabolism</topic><topic>Leukemia, Lymphocytic, Chronic, B-Cell - pathology</topic><topic>Leukemias. 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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.</abstract><cop>Washington, DC</cop><pub>Elsevier Inc</pub><pmid>20061561</pmid><doi>10.1182/blood-2009-08-239244</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis B-Lymphocytes - metabolism Biological and medical sciences Blotting, Western Case-Control Studies Cell Survival DNA Methylation Extracellular Signal-Regulated MAP Kinases - genetics Extracellular Signal-Regulated MAP Kinases - metabolism Hematologic and hematopoietic diseases Humans Leukemia, Lymphocytic, Chronic, B-Cell - genetics Leukemia, Lymphocytic, Chronic, B-Cell - metabolism Leukemia, Lymphocytic, Chronic, B-Cell - pathology Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Medical sciences Mice Mice, Knockout Promoter Regions, Genetic - genetics Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - metabolism Proto-Oncogene Proteins c-bcr - genetics Proto-Oncogene Proteins c-bcr - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger - genetics RNA, Messenger - metabolism Shc Signaling Adaptor Proteins - metabolism Signal Transduction Src Homology 2 Domain-Containing, Transforming Protein 1 |
| title | Impaired expression of p66Shc, a novel regulator of B-cell survival, in chronic lymphocytic leukemia |
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