New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic and transcriptional profiling.

Lymphomas are assumed to originate at different stages of lymphocyte development through chromosomal aberrations. Thus, different lymphomas resemble lymphocytes at distinct differentiation stages and show characteristic morphologic, genetic and transcriptional features. Here, we have performed a microarray-based DNA methylation profiling of 83 mature aggressive B-cell non-Hodgkin lymphomas (maB-NHL) characterized for their morphologic, genetic and transcriptional features, including molecular Burkitt lymphomas and diffuse large B-cell lymphomas. Hierarchical clustering indicated that methylation patterns in maB-NHL were not strictly associated with morphologic, genetic or transcriptional features. By supervised analyses, we identified 56 genes de novo methylated in all lymphoma subtypes studied and 22 methylated in a lymphoma subtype-specific manner. Remarkably, the group of genes de novo methylated in all lymphoma subtypes was significantly enriched for polycomb targets in embryonic stem cells. De novo methylated genes in all maB-NHL studied were expressed at low levels in lymphomas and normal hematopoietic tissues but not in non-hematopoietic tissues. These findings, especially the enrichment for polycomb targets in stem cells, indicate that maB-NHL with different morphological, genetic and transcriptional background share a similar stem cell-like epigenetic pattern. This suggests that maB-NHL originate from cells with stem-cell features or that stemness was acquired during lymphomagenesis by epigenetic remodeling.