Unexpected functions of nuclear factor-κB during germinal center B-cell development: implications for lymphomagenesis.

Abstract

B-cell tumors originating from the transformation of germinal center B cells frequently harbor genetic mutations, leading to constitutive activation of the nuclear factor-κB (NF-κB) signaling pathway. The present review highlights recent insights into the roles of separate NF-κB transcription factors in germinal center B-cell development and discusses implications of the results for germinal center lymphomagenesis. Understanding how aberrant NF-κB activation promotes tumorigenesis requires the understanding of the role of NF-κB in the tumor-precursor cells. Despite extensive knowledge on NF-κB biology, the function of this complex signaling pathway in the differentiation of germinal center B cells is largely unknown. The present review will discuss recent findings that revealed distinct roles of separate NF-κB transcription factors during the germinal center reaction in the context of germinal center lymphomagenesis. Most notably, a single NF-κB subunit, c-REL, was found to be required for the maintenance of the germinal center reaction and was associated with the activation of a metabolic program that promotes cell growth. Identifying the biological roles of the separate NF-κB transcription factor subunits in germinal center biology will help to better understand the pathogenic consequences of their constitutive activation in B-cell tumors. This knowledge may be exploited for the development of targeted antitumor therapies aimed at inhibiting selectively those components of aberrant NF-κB activity which contribute to pathogenesis.