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10.1038/nature24649 http://scihub22266oqcxt.onion/10.1038/nature24649 C5821214!5821214!29143824     free     free     free Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534       Nature 2017 ; 552 (7683): 121-5 Nephropedia Template TP {{tp|p=29143824|t=2017. PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis |pdf=|usr=}}{{29143824}} gab.com Text PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis JO: Nature http://www.kidney.de/pget.php?&tw=1&pmid=29143824 #FOAvip T cell non-Hodgkin lymphomas (T-NHLs) represent a heterogeneous group of highly aggressive malignancies with poor clinical outcomes1. T-NHLs originate from peripheral T lymphocytes and are frequently characterized by genetic gain-of-function variants in T cell antigen receptor (TCR) signalling molecules1?4. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and survival programmes, it remains unclear whether T cells harbour tumour suppressors that can counteract these events. Using a murine model of human T cell lymphoma, we demonstrate that the acute enforcement of oncogenic TCR signalling in lymphocytes drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor Programmed Death-1 (PD-1), as a master gene suppressing oncogenic T cell signalling. Mono- and bi-allelic PDCD1 deletions are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, PD-1 activity enhances PTEN levels and attenuates AKT and PKC signalling in pre-malignant cells. In contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Altogether, these results indicate that the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T-NHLs that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology. Twit Text FOAVip PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis ????Nature http://www.kidney.de/pget.php?&tw=1&pmid=29143824 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=29143824 #FOAvip English Wikipedia <ref>{{Cite pmid|29143824}}</ref> PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis #MMPMID29143824 Wartewig T; Kurgyis Z; Keppler S; Pechloff K; Hameister E; Öllinger R; Maresch R; Buch T; Steiger K; Winter C; Rad R; Ruland J Nature 2017[Dec]; 552 (7683): 121-5 PMID29143824show ga T cell non-Hodgkin lymphomas (T-NHLs) represent a heterogeneous group of highly aggressive malignancies with poor clinical outcomes1. T-NHLs originate from peripheral T lymphocytes and are frequently characterized by genetic gain-of-function variants in T cell antigen receptor (TCR) signalling molecules1?4. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and survival programmes, it remains unclear whether T cells harbour tumour suppressors that can counteract these events. Using a murine model of human T cell lymphoma, we demonstrate that the acute enforcement of oncogenic TCR signalling in lymphocytes drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor Programmed Death-1 (PD-1), as a master gene suppressing oncogenic T cell signalling. Mono- and bi-allelic PDCD1 deletions are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, PD-1 activity enhances PTEN levels and attenuates AKT and PKC signalling in pre-malignant cells. In contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Altogether, these results indicate that the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T-NHLs that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology. äPD-1 is a haploinsufficient suppressor of T cell lymphomagenesis (epmc).pdf DeepDyve Pubget Overpricing