Abstract 4825: Common genetic pathways are involved in canine diffuse large B cell lymphoma relapse and human diffuse large B cell lymphoma lympomagenesis
Authors: Rowell Jennie L. , Rybaczyk Leszek A. , Fenger Joelle M. , Kosarek Carrie E. , Chun Ruthanne , McNiel Elizabeth A. , Valli Victor E. , Alvarez Carlos E. , Kisseberth William C. 
Published: June 2012

Background/Purpose: The genetic complexity of lymphoma is gradually being unraveled; however, new and better approaches to a molecular understanding are needed. Dogs make an exceptional model for the study of lymphoma because lymphoma occurs spontaneously in this species with a relatively high frequency and it shares many morphological and clinical characteristics with human lymphoma. Very little is known about genetic influences on time to relapse in the most common type of lymphoma in both humans and dogs – diffuse large B-cell lymphoma (DLBCL). Thus, the aim of this study was to determine what genes and pathways are significantly correlated with time to relapse in dogs with spontaneously occurring DLBCL treated with combination chemotherapy.

Methods: Snap frozen lymph node biopsy samples were taken from dogs diagnosed with DLBCL prior to chemotherapy treatment and upon relapse. A total of 31 paired tissue samples were acquired, and a subset of 20 samples were used for this analysis. Affymetrix Canine 2.0 Genechips were used for expression profiling. Spearman's Rank Correlation (SRC) was used to detect genes correlated with clinically relevant quantitative traits. Of available measures, time to relapse provided the most power and was the most relevant to the human condition.

Results: One known pathway altered in human DLBCL involves BCL6. Our analysis found a significant gene expression signature for BCL6 pathways associated with relapsed patients (Fisher's Exact Test, p=0.0005375). Additionally, we reviewed multiple pathways associated with time to relapse and identified a novel unregulated gene- STAP1- that is highly correlated with time to relapse (r = 0.81, p=0.0000018). A protein encoded by this gene functions as a docking protein, acting downstream of Tec tyrosine kinase in B-cell antigen receptor signaling and has not been previously associated with lymphoma. NSMAF, part of the ceramide lipid signaling pathway, was also significantly correlated with patient time to relapse (r=0.76, p=.000014). NSMAF is required for TNF-mediated activation of neutral sphingomyelinase and may play a role in regulating TNF-induced cellular responses such as inflammation, proliferation, and apoptosis. Interestingly, STAP1 has been associated with lipid levels in human subjects. While further validation is required to confirm the results, these findings hint at previously unknown signaling interactions.

Conclusion: We identified genes and pathways that were significantly related to patient time to relapse in canine DLBCL. These results suggest that canine DLBCL shares molecular features with human DLBCL, but also exhibits unique interactions of signaling pathways. Taken together, this validates the dog as a model for the study of DLBCL and lends insight into pathways that may lead to the development of novel therapeutic targets.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4825. doi:10.1158/1538-7445.AM2011-4825