Use of spontaneously arising canine lymphoma as a preclinical model of DNA methylation derangements for drug target identification
Jeffrey N. Bryan University of Missouri, Missouri, USA
Abstract:
In non-Hodgkin lymphoma (nHL) DNA methylation derangements contribute to oncogenesis and disease behavior. For nHL, dogs represent a relevant model sharing important histologic and natural history similarities as well as environmental risk factors with humans. These shared nHL methylation abnormalities support developing the dog as a model for evaluating novel therapy interventions by elucidating the canine nHL methylome. DNA methylation was evaluated in the canine lymphoma cell line OSW and clinical samples of naturally occurring nHL from companion dogs. MeDIP prepared samples were hybridized against normal lymphoid tissue on gene promoter and CpG island microarray. MeDIP prepared samples were screened for gene enrichment using quantitative real-time PCR. Bisulfite-treated samples were used to confirm methylation patterns. Bioinformatic evaluation compared human and canine CpG island and promoter region structure. Like humans, dog CpG islands occur predictably in the 5’ region of genes. Patterns of CpG island hypermethylation exist in canine nHL similar to human nHL in gene families that regulate differentiation, stem function, cytoskeletal function, and transcription factor control. The results support canine nHL as a model for identifying environmental contribution to DNA methylation derangement, developing preventative dietary and drug therapies, and defining the role of demethylating therapy in nHL diseases.
Keywords:
Translational model, non-Hodgkin lymphoma, DNA methylation, dog
