Diffuse large B-cell lymphomas (DLBCL) with mutations in B-cell translocation gene 1 (BTG1) present poor outcomes and extensive dissemination. Missense mutations of BTG1 are specific to germinal center-derived B cell lymphomas, which suggests an oncogenic function that depends on the specific cellular context. In a recent study published in Science, researchers from Weill Cornell Medicine and collaborators investigated how BTG1 mutations further contribute to the pathogenesis of these tumors.