Abstract A020: Characterizing the disease pathogenesis and translational potential of naturally occurring canine small cell B cell lymphoma

Abstract

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid neoplasm in both humans and dogs and shared clinical and histopathologic features of the disease across species have supported the use of the dog as a pre-clinical translational model. Dogs present a unique model of naturally occurring disease that allows for the study of therapeutics along an accelerated lifespan relative to that of humans. While DLBCL is a well characterized disease in both dogs and humans, less common B cell lymphoma subtypes in the dog are poorly understood. Canine small cell B-cell lymphoma (BCL) is a heterogeneous disease that represents approximately 12% of BCL in dogs, but little is known about its pathogenesis and relevance as a human disease model. We hypothesized that small cell BCL in the dog also shares key molecular features with some of the rare, small cell B cell lymphomas seen in humans. To better understand the molecular drivers of small cell BCL in the dog, we performed bulk RNA sequencing and whole exome sequencing on 125 lymph node aspirates from dogs diagnosed with small cell BCL by flow cytometry. Knowing that small cell BCL in dogs carries a poor prognosis with over 50% of cases not responding to our standard of care treatments, we aim to use these molecular findings to guide testing of novel therapeutics in dogs. We hypothesize that characterization of these canine tumors and their response to novel treatments may also have translational potential if gene expression signatures or mutations are retained between the human and animal diseases. By transcriptomic analysis, most canine small cell BCL samples fell into two k-means defined clusters, while a smaller subset of samples (n=12) clustered with canine DLBCL samples. These two prominent clusters of small cell BCL show different mutational profiles, clinical features, histologic subtypes and pathway enrichment patterns. Small cell BCL Cluster 1 (n=70) is characterized by upregulation of NF-κB signaling, inflammatory responses, and B-cell receptor signaling. Small cell BCL Cluster 2 (n=39) is characterized by PI3K-AKT-mTOR signaling and higher rates of peripheral blood lymphocytosis. By genomic analysis, Cluster 2 samples had significantly higher mutation frequencies across several genes including: KMT2D, POT1, TBL1XR1, and LYN. Several of these genes are implicated in the promotion of tumor survival across various B cell lymphomas in people. Future analyses include identifying the cell of origin of these tumors, which we hypothesize will differ by cluster. These insights will influence targets for novel and repurposed therapeutics for small cell BCL in dogs and in humans if our analysis indicates these diseases are of similar molecular origins.