Non-Hodgkin lymphomas (NHL) represent a diverse group of tumors that are common in both humans and dogs. Extensive work has documented driver genes and inferred the cell of origin for many subtypes of human NHL, and emerging data suggest that the driver events are distinct for the corresponding subtypes of canine NHL. This raises important questions about how and when spontaneous canine NHLs can or should be considered as models for human NHLs. Here, we show the application of bioinformatics tools that allow us to systematically reduce the dimensionality of complex transcriptional patterns across independent datasets, platforms, and species, and that are capable of identifying conserved and unique traits, as well as outcome associations. The application of these tools to human and canine NHL datasets shows that, for example, the gene expression cluster that defines the germinal center-B-cell (GCB)-like subtype is exclusively present in human samples, but not in dog samples. Conversely, we confirm that non-GCB subtypes (activated B-cell [ABC] or ABC-like) include a heterogeneous group of subtypes defined by expression of shared and species-specific gene clusters, including resident or infiltrating cells that mold the stromal and immune microenvironments. Moreover, we are able to expand this approach to other subtypes of NHL to discern the contributions from stromal transcriptional programs and from lymphocyte transcriptional programs by including samples in the analyses where stromal cells were depleted. Overall, our comparative genomic approach will enhance our understanding of the conserved and species-specific events that underlie the molecular etiology of NHL, informing when spontaneous canine NHL subtypes should be considered as independent, unrelated conditions and improving and refining when and how they can be used as a relevant spontaneous model of human NHL.

Citation Format: Aaron L. Sarver, Jaime F. Modiano. Conserved and unique transcriptional programs in human and canine non-Hodgkin lymphomas inform the judicious applications for the spontaneous canine model of disease [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-29.