Mouse Lymphoma Model-Based Senescence Exploitation to Predict Treatment Outcome of DLBCL Patients

Introduction: Molecularly informed treatment decisions are the basis of personalized cancer precision medicine. While gene expression profiling has been used to map the molecular landscape of tumors and to study the impact of molecularly defined subtypes on treatment outcome, biological effector principles, specifically cellular senescence, remain largely understudied. Syngeneic mouse models of cancer that recapitulate core molecular features of human malignancies could serve as useful models to explore mechanisms of drug sensitivity, and, likewise, to dissect molecular mechanisms of treatment failure. In particular, we focus here on the role of therapy-induced senescence, a histone H3 lysine 9 trimethylation (H3K9me3)-governed terminal cell-cycle arrest program.

Methods: The Eµ- myc transgenic lymphoma mouse was used as a cross-species model of chemoresistance for patients diagnosed with diffuse large B-cell lymphoma (DLBCL). Gene expression profiles (GEP) of primary Eµ- myc lymphomas were obtained at diagnosis and after exposure to cyclophosphamide chemotherapy in vivo, with long-term outcome monitored in a clinical trial-like fashion. Lymphoma senescence capacity, a pivotal drug effector principle, was interrogated in mice by unbiased approaches as well as genetic perturbations.

Results: DLBCL-established gene expression-based classifiers related to cell-of-origin (COO - i.e. GCB/ABC) subtypes and distinct DLBCL biologies (e.g. comprehensive consensus clusters [CCC]) were instrumental to identify comparable lymphoma subsets in the murine system. In turn, mice carrying senescence-defective lymphomas due to engineered loss of the H3K9me3 methyltransferase Suv39h1 or overexpression of the H3K9-active demethylase LSD1 succumbed faster to chemotherapy, as DLBCL patients with high LSD1 or low H3K9me3 expression in their lymphomas presented with significantly inferior outcome. Likewise, cross-species application of senescence-associated characteristics identified in unengineered primary mouse lymphomas unveiled molecular features important for treatment outcome in human DLBCL. Ongoing mouse model-based work aims at specific targeting of aberrant H3K9 demethylase activity to assess therapeutic long-term effects and to determine the conditions for future early-phase clinical testing in DLBCL patients.

Conclusions: Primary Eµ- myc transgenic lymphomas serve as a faithful model for human DLBCL, since they share key pathologic and genetic features, including CCC/COO-based clustering. In turn, mouse lymphoma-based molecular exploration, genetic dissection and functional interrogation of treatment effector mechanisms, which is difficult to conduct in patient material, can be re-applied to molecularly and clinically co-annotated datasets from DLBCL patients to inform novel, lesion- and state-driven personalized treatment approaches and the design of future clinical trials.