By introducing a primary transgenic lymphoma model with defined genetic lesions to interrogate distinct biologies—as presented here for the Suv39h1-dependent induction of cellular senescence in response to therapy—followed by the exploration of a genetically unbiased clinical trial-like mouse lymphoma cohort, all in a syngeneic, immune-competent context, we provide a DLBCL-approximated test platform for functional investigations. Here, SUV39H1 is linked to lymphoma.