Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Wartewig, T; Kurgyis, Z; Keppler, S; Pechloff, K; Hameister, E; Öllinger, R; Maresch, R; Buch, T; Steiger, K; Winter, C; Rad, R; Ruland, J.
PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis.
Nature. 2017; 552(7683): 121-125.
Doi: 10.1038/nature24649
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- Co-Autor*innen der Med Uni Graz
- Keppler Selina Jessica
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- Abstract:
- T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events. Here we show that the acute enforcement of oncogenic TCR signalling in lymphocytes in a mouse model of human T cell lymphoma 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 that suppresses oncogenic T cell signalling. Mono- and bi-allelic deletions of PDCD1 are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, the activity of PD-1 enhances levels of the tumour suppressor PTEN and attenuates signalling by the kinases AKT and PKC in pre-malignant cells. By 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. Thus, the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T cell lymphomas 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- Carcinogenesis - genetics
- Cells, Cultured - administration & dosage
- Female - administration & dosage
- Genes, Tumor Suppressor - administration & dosage
- Haploinsufficiency - genetics
- Humans - administration & dosage
- Lymphoma, T-Cell - genetics, metabolism, pathology
- Male - administration & dosage
- Mice - administration & dosage
- Mutation - administration & dosage
- Programmed Cell Death 1 Receptor - antagonists & inhibitors, genetics, metabolism
- Signal Transduction - genetics
- T-Lymphocytes - metabolism, pathology