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

Kolja Schleich, Julia Kase, Jan R. Dörr, Saskia Trescher, Animesh Bhattacharya, Yong Yu, Elizabeth M. Wailes, Dorothy N. Y. Fan, Philipp Lohneis, Maja Milanovic, Andrea Lau, Dido Lenze, Michael Hummel, Bjoern Chapuy, Ulf Leser, Maurice Reimann, Soyoung Lee and Clemens A. Schmitt ()
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Kolja Schleich: Charité – University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum
Julia Kase: Charité – University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum
Jan R. Dörr: Charité – University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum
Saskia Trescher: Humboldt-Universität zu Berlin
Animesh Bhattacharya: Charité – University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum
Yong Yu: Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association
Elizabeth M. Wailes: Charité – University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum
Dorothy N. Y. Fan: Charité – University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum
Philipp Lohneis: University Hospital Cologne
Maja Milanovic: Charité – University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum
Andrea Lau: Charité – University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum
Dido Lenze: Charité – University Medical Center
Michael Hummel: Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner Site Berlin
Bjoern Chapuy: University Medical Center Göttingen, Department of Hematology and Medical Oncology
Ulf Leser: Humboldt-Universität zu Berlin
Maurice Reimann: Charité – University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum
Soyoung Lee: Charité – University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum
Clemens A. Schmitt: Charité – University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17467-z

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