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H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients

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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: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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