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

Autor:	Schleich K; Charité - University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353, Berlin, Germany., Kase J; Charité - University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353, Berlin, Germany., Dörr JR; Charité - University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353, Berlin, Germany., Trescher S; Institute for Computer Science, Humboldt-Universität zu Berlin, Unter Den Linden 6, 10099, Berlin, Germany., Bhattacharya A; Charité - University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353, Berlin, Germany., Yu Y; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Straße 10, 13125, Berlin, Germany., Wailes EM; Charité - University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353, Berlin, Germany., Fan DNY; Charité - University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353, Berlin, Germany.; Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner Site Berlin, Berlin, Germany., Lohneis P; University Hospital Cologne, Pathology, Kerpener Straße 62, 50937, Cologne, Germany., Milanovic M; Charité - University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353, Berlin, Germany., Lau A; Charité - University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353, Berlin, Germany., Lenze D; Charité - University Medical Center, Pathology, Charitéplatz 1, 10117, Berlin, Germany., Hummel M; Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner Site Berlin, Berlin, Germany.; Charité - University Medical Center, Pathology, Charitéplatz 1, 10117, Berlin, Germany., Chapuy B; University Medical Center Göttingen, Department of Hematology and Medical Oncology, Robert-Koch-Straße 40, 37075, Göttingen, Germany., Leser U; Institute for Computer Science, Humboldt-Universität zu Berlin, Unter Den Linden 6, 10099, Berlin, Germany., Reimann M; Charité - University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353, Berlin, Germany., Lee S; Charité - University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353, Berlin, Germany.; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Straße 10, 13125, Berlin, Germany.; Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner Site Berlin, Berlin, Germany., Schmitt CA; Charité - University Medical Center, Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, Augustenburger Platz 1, 13353, Berlin, Germany. clemens.schmitt@charite.de.; Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Straße 10, 13125, Berlin, Germany. clemens.schmitt@charite.de.; Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner Site Berlin, Berlin, Germany. clemens.schmitt@charite.de.; Kepler University Hospital, Department of Hematology and Oncology, Johannes Kepler University, Krankenhausstraße 9, 4020, Linz, Austria. clemens.schmitt@charite.de.; Berlin Institute of Health, Anna-Louisa-Karsch-Straße 2, 10178, Berlin, Germany. clemens.schmitt@charite.de.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Jul 20; Vol. 11 (1), pp. 3651. Date of Electronic Publication: 2020 Jul 20.
DOI:	10.1038/s41467-020-17467-z
Abstrakt:	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.
Databáze:	MEDLINE
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