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| Item Type: | Article |
|---|---|
| Title: | H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients |
| Creators Name: | Schleich, K. and Kase, J. and Dörr, J.R. and Trescher, S. and Bhattacharya, A. and Yu, Y. and Wailes, E.M. and Fan, D.N.Y. and Lohneis, P. and Milanovic, M. and Lau, A. and Lenze, D. and Hummel, M. and Chapuy, B. and Leser, U. and Reimann, M. and Lee, S. and Schmitt, C.A. |
| Abstract: | Lesion-based targeting strategies underlie cancer precision medicine. However, biological principles - such as cellular senescence - remain difficult to implement in molecularly informed treatment decisions. Functional analyses in syngeneic mouse models and cross-species validation in patient datasets might uncover clinically relevant genetics of biological response programs. Here, we show that chemotherapy-exposed primary Eµ-myc transgenic lymphomas - with and without defined genetic lesions - recapitulate molecular signatures of patients with diffuse large B-cell lymphoma (DLBCL). Importantly, we interrogate the murine lymphoma capacity to senesce and its epigenetic control via the histone H3 lysine 9 (H3K9)-methyltransferase Suv(ar)39h1 and H3K9me3-active demethylases by loss- and gain-of-function genetics, and an unbiased clinical trial-like approach. A mouse-derived senescence-indicating gene signature, termed "SUVARness", as well as high-level H3K9me3 lymphoma expression, predict favorable DLBCL patient outcome. Our data support the use of functional genetics in transgenic mouse models to incorporate basic biology knowledge into cancer precision medicine in the clinic. |
| Keywords: | 3T3 Cells, Animal Disease Models, Cellular Senescence, Diffuse Large B-Cell Lymphoma, Genetic Epigenesis, Gene Expression Profiling, Histone Methyltransferases, Neoplastic Gene Expression Regulation, Prognosis, Transgenic Mice, Tumor Cell Line, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 11 |
| Number: | 1 |
| Page Range: | 3651 |
| Date: | 20 July 2020 |
| Official Publication: | https://doi.org/10.1038/s41467-020-17467-z |
| PubMed: | View item in PubMed |
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