Role of chromosomal architecture in germinal center B cells and lymphomagenesis

Chromatin organization during interphase is nonrandom, and dictated by a delicate equilibrium between biophysics, transcription factor expression, and topological regulators of the chromatin. Emerging evidence demonstrate a role for chromosomal conformation at different stages of B-cell development. In the present review, we provide an updated picture of the current knowledge regarding how chromosomal conformation regulates the B-cell phenotype and how disruption of this architecture could lead to B-cell lymphoma.

B-cell development requires proper assembly of a rearranged VDJ locus, which will determine antigen receptor specificity. Recently, evidence pointed to a role for topological regulators during VDJ recombination. Research studies also demonstrated a link between shifts in nuclear chromosomal architecture during B-cell activation and in formation of germinal centers, which is required for immunoglobulin affinity maturation. Class-switch recombination was shown to be dependent on the presence of topology regulators. Loss of topological insulation of enhancers may lead to oncogene activation, suggesting that misfolding of chromatin may constitute a new epigenetic mechanism of malignant transformation. Finally, CCCTC-binding factor and cohesin binding sites have shown a higher probability of mutations and translocations in lymphomas, lending further support to the potential role of chromatin architecture in cancer development.

Chromosomal conformation is now recognized as a key feature in the development of a robust humoral immune response. Several examples from the literature show that dysregulation of chromosomal architecture may be a foundational event during malignancy. Therefore, understanding the mechanisms that regulate chromosomal folding and drive gene activation are instrumental for a better understanding of immune regulation and lymphomagenesis.