Molecular pathogenesis of diffuse large B-cell lymphoma

Abstract

In past years, substantial insight regarding the pathogenesis of diffuse large B-cell lymphoma has been obtained. Particularly, based on gene expression profile analysis, this disease can be classified into distinct phenotypic subgroups and specific transcriptional programs have been identified. New technologies like next-generation whole genome/exome sequencing and genome-wide single nucleotide polymorphism array analysis have revealed novel lesions involved in the pathogenesis of this disease. This review focuses on the diversity of genetic lesions identified in the different subtypes of diffuse large B-cell lymphoma.

Figure 1

The germinal center reaction Upon T-cell dependent antigen stimulation, naïve B-cells migrate to secondary lymphoid organs, differentiate into centroblasts, and proliferate in the dark zone of the germinal centers. Within the dark zone, the centroblasts undergo somatic hypermutation (SHM), which introduces mostly single base-pair changes into the immunoglobulin variable region of the heavy and light chain locus, with the aim of increasing their affinity for the antigen. Centroblasts then move to the light zone, where they differentiate into centrocytes and undergo class-switch recombination (CSR). T-cells and follicular dendritic cells help to re-challenge the centrocytes with the antigen such that cells with a low-affinity immunoglobulin-receptor are eliminated by apoptosis, while a subset of centrocytes with high-affinity to the antigen are selected to differentiate further into memory B-cells or plasma cells.

Figure 2

Oncogenic pathways in ABC-DLBCL The stimulation of several surface receptors, including the B-cell receptor (BCR), CD40 or Toll-like receptors, triggers signaling cascades resulting in the activation of the NF-kB pathway. In ABC-DLBCL, NF-kB is constitutively activated and several genetic lesions that contribute to this activation have been identified.