Constitutive activation of mTOR signaling pathway in post-transplant lymphoproliferative disorders
We examined activation of the mTOR signaling pathway in situ in the primary, normal reactive and patient-derived post-transplant lymphoproliferative disorder (PTLD) tissue samples. We accomplished this analysis by immunohistochemistry on formalin-fixed, paraffin-embedded specimens using a set of hig...
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Veröffentlicht in: | Laboratory investigation 2007-01, Vol.87 (1), p.29-39 |
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description | We examined activation of the mTOR signaling pathway in situ in the primary, normal reactive and patient-derived post-transplant lymphoproliferative disorder (PTLD) tissue samples. We accomplished this analysis by immunohistochemistry on formalin-fixed, paraffin-embedded specimens using a set of highly specific antibodies that permitted us to determine phosphorylation status of the key serines in the mTOR target proteins. Our results demonstrate that the mTOR signaling pathway is activated in reactive tissue in a highly distinct fashion with positive, typically enlarged cells being present primarily in the germinal center and, to a lesser degree, in interfollicular areas with mantle zone being conspicuously negative. We could demonstrate mTOR activation in the lesional cells in the entire spectrum of PTLD subtypes, regardless of their Epstein–Barr virus genome expression status. These data demonstrate the ubiquitous activation of the mTOR signaling pathway in PTLD and indicate that mTOR inhibitors may be effective in treatment and, notably, prevention of PTLDs given their immunosuppressive properties. Furthermore, our results define potential biomarkers of the therapeutic response. Because the constitutive mTOR activation has also been identified in cells isolated from other hematologic malignancies, the ability to examine the in vivo mTOR signaling may have implications reaching beyond the PTLD field. |
doi_str_mv | 10.1038/labinvest.3700494 |
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We accomplished this analysis by immunohistochemistry on formalin-fixed, paraffin-embedded specimens using a set of highly specific antibodies that permitted us to determine phosphorylation status of the key serines in the mTOR target proteins. Our results demonstrate that the mTOR signaling pathway is activated in reactive tissue in a highly distinct fashion with positive, typically enlarged cells being present primarily in the germinal center and, to a lesser degree, in interfollicular areas with mantle zone being conspicuously negative. We could demonstrate mTOR activation in the lesional cells in the entire spectrum of PTLD subtypes, regardless of their Epstein–Barr virus genome expression status. These data demonstrate the ubiquitous activation of the mTOR signaling pathway in PTLD and indicate that mTOR inhibitors may be effective in treatment and, notably, prevention of PTLDs given their immunosuppressive properties. Furthermore, our results define potential biomarkers of the therapeutic response. Because the constitutive mTOR activation has also been identified in cells isolated from other hematologic malignancies, the ability to examine the in vivo mTOR signaling may have implications reaching beyond the PTLD field.</description><identifier>ISSN: 0023-6837</identifier><identifier>EISSN: 1530-0307</identifier><identifier>DOI: 10.1038/labinvest.3700494</identifier><identifier>PMID: 17075574</identifier><identifier>CODEN: LAINAW</identifier><language>eng</language><publisher>New York: Elsevier Inc</publisher><subject>4E-binding protein 1 ; Adaptor Proteins, Signal Transducing - metabolism ; Biological and medical sciences ; Biotechnology ; Cell Cycle Proteins ; Cell Line, Tumor ; Epstein-Barr virus ; eukaryotic initiation factor 4G ; Eukaryotic Initiation Factor-4G - metabolism ; Fundamental and applied biological sciences. Psychology ; Humans ; Immunohistochemistry ; Investigative techniques, diagnostic techniques (general aspects) ; Laboratory Medicine ; Lymphoproliferative Disorders - metabolism ; mammalian target of rapamycin ; Medical sciences ; Medicine ; Medicine & Public Health ; Organ Transplantation - adverse effects ; Pathology ; Phosphoproteins - metabolism ; post-transplant lymphoproliferative disorder ; Protein Kinases - metabolism ; rapamycin ; research-article ; Ribosomal Protein S6 - metabolism ; S6 ribosomal protein ; Signal Transduction - physiology ; Sirolimus - pharmacology ; TOR Serine-Threonine Kinases</subject><ispartof>Laboratory investigation, 2007-01, Vol.87 (1), p.29-39</ispartof><rights>2007 United States & Canadian Academy of Pathology</rights><rights>United States and Canadian Academy of Pathology, Inc. 2007</rights><rights>2007 INIST-CNRS</rights><rights>Copyright Nature Publishing Group Jan 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c614t-6fed235cf6e8e233c4f1853f4c968c13cc91da1fb8036ead4eb931b3a95c77113</citedby><cites>FETCH-LOGICAL-c614t-6fed235cf6e8e233c4f1853f4c968c13cc91da1fb8036ead4eb931b3a95c77113</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18572965$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17075574$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>El-Salem, Mouna</creatorcontrib><creatorcontrib>Raghunath, Puthiyaveettil N</creatorcontrib><creatorcontrib>Marzec, Michal</creatorcontrib><creatorcontrib>Wlodarski, Pawel</creatorcontrib><creatorcontrib>Tsai, Donald</creatorcontrib><creatorcontrib>Hsi, Eric</creatorcontrib><creatorcontrib>Wasik, Mariusz A</creatorcontrib><title>Constitutive activation of mTOR signaling pathway in post-transplant lymphoproliferative disorders</title><title>Laboratory investigation</title><addtitle>Lab Invest</addtitle><addtitle>Lab Invest</addtitle><description>We examined activation of the mTOR signaling pathway in situ in the primary, normal reactive and patient-derived post-transplant lymphoproliferative disorder (PTLD) tissue samples. We accomplished this analysis by immunohistochemistry on formalin-fixed, paraffin-embedded specimens using a set of highly specific antibodies that permitted us to determine phosphorylation status of the key serines in the mTOR target proteins. Our results demonstrate that the mTOR signaling pathway is activated in reactive tissue in a highly distinct fashion with positive, typically enlarged cells being present primarily in the germinal center and, to a lesser degree, in interfollicular areas with mantle zone being conspicuously negative. We could demonstrate mTOR activation in the lesional cells in the entire spectrum of PTLD subtypes, regardless of their Epstein–Barr virus genome expression status. These data demonstrate the ubiquitous activation of the mTOR signaling pathway in PTLD and indicate that mTOR inhibitors may be effective in treatment and, notably, prevention of PTLDs given their immunosuppressive properties. Furthermore, our results define potential biomarkers of the therapeutic response. Because the constitutive mTOR activation has also been identified in cells isolated from other hematologic malignancies, the ability to examine the in vivo mTOR signaling may have implications reaching beyond the PTLD field.</description><subject>4E-binding protein 1</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Biological and medical sciences</subject><subject>Biotechnology</subject><subject>Cell Cycle Proteins</subject><subject>Cell Line, Tumor</subject><subject>Epstein-Barr virus</subject><subject>eukaryotic initiation factor 4G</subject><subject>Eukaryotic Initiation Factor-4G - metabolism</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Investigative techniques, diagnostic techniques (general aspects)</subject><subject>Laboratory Medicine</subject><subject>Lymphoproliferative Disorders - metabolism</subject><subject>mammalian target of rapamycin</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Organ Transplantation - adverse effects</subject><subject>Pathology</subject><subject>Phosphoproteins - metabolism</subject><subject>post-transplant lymphoproliferative disorder</subject><subject>Protein Kinases - metabolism</subject><subject>rapamycin</subject><subject>research-article</subject><subject>Ribosomal Protein S6 - metabolism</subject><subject>S6 ribosomal protein</subject><subject>Signal Transduction - physiology</subject><subject>Sirolimus - pharmacology</subject><subject>TOR Serine-Threonine Kinases</subject><issn>0023-6837</issn><issn>1530-0307</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kU9r3DAQxUVpaLbbfoAeWkwhzcmpZMn_6KksbRMIBEp6NrI82ijYkquRt-y3jzY2WehhT3OY33savUfIB0avGOXV1162xu4AwxUvKRW1eEVWLOc0pZyWr8mK0oynRcXLc_IW8ZFSJkSRvyHnrKRlnpdiRdqNsxhMmILZQSJVHDIYZxOnk-H-7neCZmtlb-w2GWV4-Cf3ibHJ6DCkwUuLYy9tSPr9MD640bveaPDy2asz6HwHHt-RMy17hPfLXJM_P3_cb67T27tfN5vvt6kqmAhpoaHLeK50ARVknCuhWZVzLVRdVIpxpWrWSabbivICZCegrTlruaxzVZaM8TW5nH3jHX-nmEozGFTQxwvBTdjEHzPO65jcmnw5SR4io3V1sPz8H_joJh_zwCbLaFaL4hliM6S8Q_Sgm9GbQfp9w2hz6Kl56alZeoqaT4vx1A7QHRVLMRG4WACJSvY6Zq0MHrkqL7O6yCOXzRzGld2CP1546vWPs8jKMHl4cT3uv817iHXtTDRFZcAq6IwHFZrOmRPuT4KRzuE</recordid><startdate>20070101</startdate><enddate>20070101</enddate><creator>El-Salem, Mouna</creator><creator>Raghunath, Puthiyaveettil N</creator><creator>Marzec, Michal</creator><creator>Wlodarski, Pawel</creator><creator>Tsai, Donald</creator><creator>Hsi, Eric</creator><creator>Wasik, Mariusz A</creator><general>Elsevier Inc</general><general>Nature Publishing Group US</general><general>Nature Publishing</general><general>Nature Publishing Group</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>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20070101</creationdate><title>Constitutive activation of mTOR signaling pathway in post-transplant lymphoproliferative disorders</title><author>El-Salem, Mouna ; Raghunath, Puthiyaveettil N ; Marzec, Michal ; Wlodarski, Pawel ; Tsai, Donald ; Hsi, Eric ; Wasik, Mariusz A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c614t-6fed235cf6e8e233c4f1853f4c968c13cc91da1fb8036ead4eb931b3a95c77113</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>4E-binding protein 1</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Biological and medical sciences</topic><topic>Biotechnology</topic><topic>Cell Cycle Proteins</topic><topic>Cell Line, Tumor</topic><topic>Epstein-Barr virus</topic><topic>eukaryotic initiation factor 4G</topic><topic>Eukaryotic Initiation Factor-4G - metabolism</topic><topic>Fundamental and applied biological sciences. 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Academic</collection><jtitle>Laboratory investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>El-Salem, Mouna</au><au>Raghunath, Puthiyaveettil N</au><au>Marzec, Michal</au><au>Wlodarski, Pawel</au><au>Tsai, Donald</au><au>Hsi, Eric</au><au>Wasik, Mariusz A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Constitutive activation of mTOR signaling pathway in post-transplant lymphoproliferative disorders</atitle><jtitle>Laboratory investigation</jtitle><stitle>Lab Invest</stitle><addtitle>Lab Invest</addtitle><date>2007-01-01</date><risdate>2007</risdate><volume>87</volume><issue>1</issue><spage>29</spage><epage>39</epage><pages>29-39</pages><issn>0023-6837</issn><eissn>1530-0307</eissn><coden>LAINAW</coden><abstract>We examined activation of the mTOR signaling pathway in situ in the primary, normal reactive and patient-derived post-transplant lymphoproliferative disorder (PTLD) tissue samples. We accomplished this analysis by immunohistochemistry on formalin-fixed, paraffin-embedded specimens using a set of highly specific antibodies that permitted us to determine phosphorylation status of the key serines in the mTOR target proteins. Our results demonstrate that the mTOR signaling pathway is activated in reactive tissue in a highly distinct fashion with positive, typically enlarged cells being present primarily in the germinal center and, to a lesser degree, in interfollicular areas with mantle zone being conspicuously negative. We could demonstrate mTOR activation in the lesional cells in the entire spectrum of PTLD subtypes, regardless of their Epstein–Barr virus genome expression status. These data demonstrate the ubiquitous activation of the mTOR signaling pathway in PTLD and indicate that mTOR inhibitors may be effective in treatment and, notably, prevention of PTLDs given their immunosuppressive properties. Furthermore, our results define potential biomarkers of the therapeutic response. Because the constitutive mTOR activation has also been identified in cells isolated from other hematologic malignancies, the ability to examine the in vivo mTOR signaling may have implications reaching beyond the PTLD field.</abstract><cop>New York</cop><pub>Elsevier Inc</pub><pmid>17075574</pmid><doi>10.1038/labinvest.3700494</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | 4E-binding protein 1 Adaptor Proteins, Signal Transducing - metabolism Biological and medical sciences Biotechnology Cell Cycle Proteins Cell Line, Tumor Epstein-Barr virus eukaryotic initiation factor 4G Eukaryotic Initiation Factor-4G - metabolism Fundamental and applied biological sciences. Psychology Humans Immunohistochemistry Investigative techniques, diagnostic techniques (general aspects) Laboratory Medicine Lymphoproliferative Disorders - metabolism mammalian target of rapamycin Medical sciences Medicine Medicine & Public Health Organ Transplantation - adverse effects Pathology Phosphoproteins - metabolism post-transplant lymphoproliferative disorder Protein Kinases - metabolism rapamycin research-article Ribosomal Protein S6 - metabolism S6 ribosomal protein Signal Transduction - physiology Sirolimus - pharmacology TOR Serine-Threonine Kinases |
title | Constitutive activation of mTOR signaling pathway in post-transplant lymphoproliferative disorders |
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