Simplified models of lymphomagenesis of maB-NHL integrating the data generated in the present study. (A) Commonly accepted genetic model of lymphomagenesis in which a chromosomal aberration is the primary immortalizing hit followed by additional genetic and epigenetic events. (B) Epigenetic origin of maB-NHL in which aberrant methylation of PcG target genes in stem or progenitor cells is the initial hit in lymphomagenesis. Subsequently, these cells acquire chromosomal aberrations followed by additional genetic and epigenetic changes to give rise to specific subtypes of maB-NHL. (C) Genetic origin of maB-NHL in which an initial chromosomal aberration takes place either in a stem or precursor cells (C1) or in differentiating cells (C2). A prerequisite for aberrant DNA methylation of PcG targets is the binding of PcG proteins to stem cell–related target genes, which can be acquired through the cell type in which the translocation occurs (C1) or through reprogramming a somatic differentiating cell into a cell with stem cell–like features (C2). After this, cells would acquire aberrant DNA methylation of PcG target genes followed by additional genetic and epigenetic hits that finally result into a maB-NHL.