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

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 with significantly longer survival times. Further transcriptomics-based investigations of our clinical-trial like mouse model and DLBCL patients suggests the presence of a molecular network distinguishing lymphomas into a clinically superior senescence responder from an inferior non-responder group.

Conclusions: Our results conclude that Eµ-myc transgenic lymphomas serve as faithful model for human DLBCL and the importance of therapy-induced senescence for treatment outcome of DLBCL patients. Our data suggest the integration of tractable, transgenic mouse models to the repertoire of functional test platforms to better implement lesion- and state-based decisions in personalized cancer precision medicine. Ongoing mouse model-based work aims at specific targeting of aberrant demethylase activities and synthetic lethal approaches to selectively eliminate potentially detrimental senescent lymphoma cells after chemotherapy to assess therapeutic long-term effects and to determine the conditions for future early-phase DLBCL clinical testing.