Concept of the cellular origin of t(14;18)-positive DLBCL.

The t(14;18) occurs as a rare random event in naive B cells, probably during the D/J rearrangement of the IGH gene. Such a B cell may encounter the appropriate antigen in the context of dendritic cells and T cells in the paracortical region of a lymph node. The stimulated B cell then migrates to and proliferates in a GC. Overexpression of bcl-2 protein protects the cell and its progeny from apoptosis even when the affinity of the antibody is not very high. Repeated cycles of proliferation from subsequent antigenic encounters expand this clone and result in additional genetic abnormalities. Different secondary genetic alterations lead to the development of a primary DLBCL (A) or a follicular lymphoma (B). Further genetic changes occurring during the course of a follicular lymphoma will give rise to a secondary DLBCL in some cases (C). A number of genes may be able to initiate each of these pathways and the gene expression profile may be unique and distinguishable for each.