Universität zu Köln

Schleich, Kolja, Kase, Julia, Doerr, Jan R., Trescher, Saskia, Bhattacharya, Animesh, Yu, Yong, Wailes, Elizabeth M., Fan, Dorothy N. Y., Lohneis, Philipp, Milanovic, Maja, Lau, Andrea, Lenze, Dido, Hummel, Michael, Chapuy, Bjoern, Leser, Ulf, Reimann, Maurice, Lee, Soyoung ORCID: 0000-0002-4614-2931 and Schmitt, Clemens A. (2020). H3K9me3-mediated epigenetic regulation of senescence in mice predicts outcome of lymphoma patients. Nat. Commun., 11 (1). LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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 E mu-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. Therapy-induced senescence reflects a biological effector principle that is underrecognized in lesion-focused cancer precision medicine. Here the authors utilize mouse lymphoma genetics to functionally dissect senescence and cross-species apply a novel senescence-based prognosticator to lymphoma patients.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schleich, Kolja UNSPECIFIED UNSPECIFIED UNSPECIFIED Kase, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Doerr, Jan R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Trescher, Saskia UNSPECIFIED UNSPECIFIED UNSPECIFIED Bhattacharya, Animesh UNSPECIFIED UNSPECIFIED UNSPECIFIED Yu, Yong UNSPECIFIED UNSPECIFIED UNSPECIFIED Wailes, Elizabeth M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fan, Dorothy N. Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lohneis, Philipp UNSPECIFIED UNSPECIFIED UNSPECIFIED Milanovic, Maja UNSPECIFIED UNSPECIFIED UNSPECIFIED Lau, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Lenze, Dido UNSPECIFIED UNSPECIFIED UNSPECIFIED Hummel, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Chapuy, Bjoern UNSPECIFIED UNSPECIFIED UNSPECIFIED Leser, Ulf UNSPECIFIED UNSPECIFIED UNSPECIFIED Reimann, Maurice UNSPECIFIED UNSPECIFIED UNSPECIFIED Lee, Soyoung UNSPECIFIED orcid.org/0000-0002-4614-2931 UNSPECIFIED Schmitt, Clemens A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-326061
DOI:	10.1038/s41467-020-17467-z
Journal or Publication Title:	Nat. Commun.
Volume:	11
Number:	1
Date:	2020
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	2041-1723
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language B-CELL LYMPHOMA; NF-KAPPA-B; ELDERLY-PATIENTS; DISTINCT TYPES; EXPRESSION; DEMETHYLASES; PATHOGENESIS; MUTATIONS; RITUXIMAB; PROMOTES Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32606