Senescence Markers from a DLBCL-Reminiscent Mouse Lymphoma Model Predict Patient Outcome

• Published in: Blood 2018-11, Vol.132 (Supplement 1), p.2850-2850
• Main Authors: Schleich, Kolja, Kase, Julia, Dörr, Jan R., Trescher, Saskia, Battacharya, Animesh, Yu, Yong, Lohneis, Philipp, Lenze, Dido, Fan, Dorothy Ngo-Yin, Hummel, Michael, Leser, Ulf, Schmitt, Clemens A.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-99-118002

Introduction: Treatment decisions based on patient-specific molecular features are central to personalized cancer precision medicine. Oftentimes treatment response of an individual patient remains an issue of trial and error. Expression profiling has been utilized to study molecular subtypes of tumor entities and their impact on treatment outcome. Biological effector programs, such as cellular senescence, however, remain largely understudied. Syngeneic mouse models of cancer that can reproduce critical molecular features of human malignancies could serve as useful models to explore genetic determinants of drug sensitivity, and, likewise, to unveil molecular mechanisms of treatment resistance. Here, we focus on the involvement of therapy-induced senescence on treatment outcome in mouse models and patients diagnosed with diffuse large B-cell lymphoma (DLBCL). Methods: We present and characterize here the utilization of Eµ-myc transgenic lymphomas as a faithful model of chemoresistance and demonstrate its cross-species validity for DLBCL patients. Specifically, primary Eµ-myc lymphomas, of which we generated gene expression profiles (GEP) at diagnosis, were exposed to genotoxic therapy in vivo, and subsequently monitored regarding long-term outcome in a clinical trial-like design. Lymphoma senescence capability, a central drug effector principle, was studied in mice by unbiased approaches as well as loss- and gain-of-function genetics. Results: Investigation of DLBCL-established gene expression based subtypes related to cell-of-origin (COO - i.e. GCB/ABC subtypes) and distinct DLBCL biologies (e.g. comprehensive consensus clusters [CCC]) using machine-learning methods demonstrated their relevance in the murine platform. Moreover, our findings show an important role of histone H3 lysine 9-trimethylation (H3K9me3) for senescence induction and treatment outcome as demonstrated by shorter time to death and time to relapse of mice bearing lymphomas with engineered loss of the H3K9me3-critical methyltransferase Suv39h1 on one hand and lymphomas with genetically transferred or endogenous overexpression of H3K9-active demethylases on the other hand. Furthermore, expression levels of H3K9me3-specific demethylases stratified unmodified Eµ-myc lymphomas and DLBCL patients into two groups with superior outcome for those with lower levels. In line with these findings, DLBCL patients with high levels of the senescence-associated H3K9me3 mark in their lymphomas presented wi