Rewired NFκB signaling as a potentially actionable feature of activated B‐cell‐like diffuse large B‐cell lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma in the Western world and remains a clinical challenge. Two types of DLBCL are distinguishable, namely a germinal center B-cell-like phenotype (GCB) and an activated B-cell-like phenotype (ABC). Particularly ABC-DLBCL is difficult to treat, as this subentity typically displays resistance against frontline chemo-immune therapy. Through the availability of novel experimental technologies, such as next-generation sequencing and cutting-edge mouse models, we recently caught an unprecedentedly detailed glimpse at the genomic and biological features of ABC-DLBCL. Currently, a picture is emerging which suggests that ABC-DLBCL critically depends on sustained activity of the NFjB pathway, which, among others, is achieved through numerous distinct genetic aberrations, including CD79A/B-, CARD11-, and MYD88 mutations. Further genomic aberrations include amplifications of BCL2 and inactivating mutations in PRMD1. These molecular insights have spurred the development of novel autochthonous mouse models that faithfully mimic the biology and genetics of human ABC-DLBCL and could serve as preclinical platforms in future experiments. Furthermore, our genomic understanding of the disease now enables us to develop and validate novel targeted therapeutic intervention strategies that aim at decapitating non-physiological NFjB activity and repressing anti-apoptotic BCL2 signaling. In this review, we highlight these recent developments and make suggestions for further tool development and the design and stratification of future clinical trials.

NFKB2 gene expression in patients with peptic ulcer diseases and gastric cancer

“…The aim of the study was to determine the level of NFKB2 mRNA in peptic ulcer and gastric cancer and compare the obtained results to control tissue, including other important clinical parameters, like presence of H. pylori infection, TNM staging and others. Inappropriate NFKB2 activation as a recurrent feature is well documented in MALT lymphomas, PMBL, multiple myeloma, and Hodgkin's lymphoma [13][14][15][16] and solid tumours [17,18]. In our study we showed that the level of mRNA is lower in patients with gastric cancer when compared to the control tissue or patients with peptic ulcer.…”

Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses

“…HOIPINs induce cell death in B cell lymphoma cell lines. In diffuse large B cell lymphoma (DLBCL), activated B cell-like DLBCL (ABC-DLBCL) is reportedly induced by constitutively elevated NF-κB activation, whereas the germinal center B cell-like DLBCL (GCB-DLBCL) is associated with defects in chromatin remodeling 44,45 . Importantly, the polymorphisms in HOIP are closely associated with ABC-DLBCL 23 .…”

Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma

“…Nevertheless, these results are important in the context of the typically inferior outcomes seen in patients with non-GCB-derived DLBCL (4,38). A potential hypothesis for this apparently greater benefit of MRV in patients with non-GCB-derived DLBCL is that activated B-cell (ABC)-derived DLBCL is characterized by constitutive nuclear factor-kappa-B pathway (NF-kB) activation (44) and that there is cross-talk between the AAK and NF-kB pathways; as reported in epithelial ovarian cancer stem cells, which also have constitutive NF-kB activation, AAK inhibition resulted in cell-cycle arrest, NF-kB inhibition, and decreased cytokine production, thereby decreasing cell proliferation (45). AAK inhibition may thus be hypothesized to have specific activity in the setting of constitutive NF-kB activation.…”