Aberrant Activation of NF-κB Signalling in Aggressive Lymphoid Malignancies

Abstract

Lymphoid malignancies frequently harbor genetic mutations leading to aberrant activation of nuclear factor-κB (NF-κB) signaling; in normal cells, this pathway has important roles in the control of cell growth, survival, stress responses, and inflammation. Malignancies with mutations in NF-κB pathway components can derive from all cell stages of mature B-cell development; however, aberrant NF-κB activity is particularly prevalent in aggressive subtypes of non-Hodgkin lymphoma and myeloma. NF-κB activation is mediated by two separate pathways, the canonical and alternative pathway, and five downstream transcription factor subunits. Recent findings implicate a predominant role for distinct NF-κB pathways and subunits in certain lymphoma subtypes and myeloma; findings which are complemented by the realization that individual NF-κB subunits can have unique, non-redundant biological roles in the putative tumor precursor cells, including activated B cells, germinal center B cells and plasma cells. The knowledge gained from these studies may be exploited for the development of therapeutic strategies to inhibit aberrant NF-κB activity at the level of the transcription-factor subunits and their target genes, as global inhibition of the pathway is toxic. Here, we provide an overview on the role of aberrant NF-κB activation in aggressive lymphoid malignancies and discuss the potential importance of individual NF-κB subunits in the pathogenesis of tumor subtypes.

What Will B Will B: Identifying Molecular Determinants of Diverse B-Cell Fate Decisions Through Systems Biology

“…Subsequent cRel downregulation is required to complete differentiation ( Roy et al, 2019 ). The distinct roles of NF-κB cRel and RelA in B-cell survival and differentiation, respectively, seen in these multiscale models are consistent with in vivo requirements for germinal center maintenance and plasma cell generation ( Heise et al, 2014 ) and an emerging picture of subunit-specific dysregulation of NF-κB in lymphoid malignancies ( Kennedy and Klein, 2018 ).…”

Expression pattern of histone lysine‑specific demethylase 6B in gastric cancer

“…Ha et al (33) reported that KMD6B can promote G 1 /S phase arrest in THP-1 cells. KMD6B mediates the malignant progression of diffuse large B cell lymphoma by sustaining the activation of the NF-κB pathway via interacting with the transcription factor IRF4 and also can promote apoptosis resistance and cell proliferation (22,34,35). The present study demonstrated that GSK J4 significantly inhibited the proliferation of HGC27 gastric cancer cells as the percent of cells in the G 2 phase was increased in GSK J4-treated groups, the expression of cyclin B1 and Cdc2 was significantly decreased and p21 was upregulated.…”

TET2 deficiency reprograms the germinal center B cell epigenome and silences genes linked to lymphomagenesis

“…4A and table S6). These include BATF (B-cell-activating transcription factor), which is a basic leucine zipper TF that activates expression of activationinduced cytidine deaminase (AID) through the recruitment of the TET2 and TET3 proteins (29); interferon regulatory factor 4 (IRF4), which is the master regulator of the GC exit program (30); and nuclear factor B 1 (NF-B1) and NF-B2, which are downstream of the B cell-activating pathways induced by B cell receptor and CD40 (31). We also observed enrichment of PU.1:IRF8 hybrid sites; notably, PU.1 has been shown to activate gene expression via recruitment of TET proteins in normal pro-B cells (29,32).…”