Conserved Regulatory DNA Methylation in Human and MYC/PI3K-Driven Murine EBV-Negative Burkitt Lymphoma

Background/Objectives: Burkitt lymphoma (BL) is an aggressive germinal center B-cell (gcBC) malignancy driven by MYC deregulation and cooperating molecular alterations. A mouse model combining constitutive MYC and PI3K activity in gcBC closely recapitulates key features of human BL, but its epigenetic similarity to the human disease has not been investigated in detail. Here, we compared genome-wide DNA methylation patterns between human sporadic EBV-negative BL and this murine model. Methods: DNA methylation profiles of 37 human BL samples and 20 gcBC controls were compared with those of 8 murine tumors from the MYC/PI3K driven mouse model and 11 murine gcBC controls using Illumina methylation arrays. Differentially methylated CpGs were identified using linear modeling, and chromatin-state enrichment, cross-species gene overlap, protein interaction, and pathway enrichment analyses were performed. Results: BL showed global DNA hypomethylation in both species and distinct methylation profiles from gcBCs. CpGs hypomethylated in BL were enriched at enhancers, whereas hypermethylated CpGs were strongly enriched at poised promoters. We identified 695 genes with shared hypermethylation and 512 with shared hypomethylation between human and murine BL. Restricting the analysis to regulatory regions identified 86 genes consistently hypomethylated in both species. These genes were significantly enriched for regulation of intracellular signal transduction and sphingolipid signaling. Included are regulators of GTPase and kinase signaling, such as GNA13, RASA3, RASAL1, SPRED2, PIK3R2, PRKCA, PRKCE, and FYN. The conserved set also contained genes with established roles in germinal center B-cell biology, including FOXO1, BACH2, and NR3C1. Conclusions: Human and murine BL share conserved regulatory DNA methylation features, supporting the MYC/PI3K mouse model as a system to study epigenetic mechanisms of BL.