NF-κB: blending metabolism, immunity, and inflammation.

Most B cell lymphomas arise from the oncogenic transformation of B cells that have undergone the germinal center (GC) reaction of the T cell-dependent immune response, where high-affinity memory B cells and plasma cells are generated. The high proliferation of GC B cells coupled with occasional errors in the DNA-modifying processes of somatic hypermutation and class switch recombination put the cell at a risk to obtain transforming genetic aberrations, which may activate proto-oncogenes or inactivate tumour suppressor genes. Several subtypes of GC lymphomas harbor genetic mutations leading to constitutive, aberrant activation of the nuclear factor-κB (NF-κB) signaling pathway. In normal B cells, NF-κB has crucial biological roles in development and physiology. GC lymphomas highjack these activities to promote tumour-cell growth and survival. It has become increasingly clear that the separate canonical and non-canonical routes of the NF-κB pathway and the five downstream NF-κB transcription factors have distinct functions in the successive stages of GC B-cell development. These findings may have direct implications for understanding how aberrant NF-κB activation promotes the genesis of various GC lymphomas corresponding to the developmentally distinct GC B-cell subsets. The knowledge arising from these studies may be explored for the development of precision medicine approaches aimed at more effective treatments of the corresponding tumours with specific NF-κB inhibitors, thus reducing systemic toxicity. We here provide an overview on the patterns of genetic NF-κB mutations encountered in the various GC lymphomas and discuss the consequences of aberrant NF-κB activation in those malignancies as related to the biology of NF-κB in their putative normal cellular counterparts.

/pdf/nf-kb-mutations-in-germinal-center-b-cell-lymphomas-relation-3nub0g3f.pdf

NF-κB Mutations in Germinal Center B-Cell Lymphomas: Relation to NF-κB Function in Normal B Cells

Abstract The nuclear factor kappa B (NF-κB) family of transcription factors orchestrates signal-induced gene expression in diverse cell types. Cellular responses to NF-κB activation are regulated at the level of cell and signal specificity, as well as differential use of family members (subunit specificity). Here we used time-dependent multi-omics to investigate the selective functions of Rel and RelA, two closely related NF-κB proteins, in primary B lymphocytes activated via the B cell receptor. Despite large numbers of shared binding sites genome wide, Rel and RelA directed kinetically distinct cascades of gene expression in activated B cells. Single-cell RNA sequencing revealed marked heterogeneity of Rel- and RelA-specific responses, and sequential binding of these factors was not a major mechanism of protracted transcription. Moreover, nuclear co-expression of Rel and RelA led to functional antagonism between the factors. By rigorously identifying the target genes of each NF-κB subunit, these studies provide insights into exclusive functions of Rel and RelA in immunity and cancer. 

NF-κB subunits direct kinetically distinct transcriptional cascades in antigen receptor-activated B cells

http://www.cell.com/article/S2211124722003278/pdf

Ligand-independent oligomerization of TACI is controlled by the transmembrane domain and regulates proliferation of activated B cells.

Chronic immunopathology contributes to the development of heart failure after a myocardial infarction. Both T and B cells of the adaptive immune system are present in the myocardium and have been suggested to be involved in post-MI immunopathology. 

Persistent transcriptional changes in cardiac adaptive immune cells following myocardial infarction: New evidence from the re-analysis of publicly available single cell and nuclei RNA-sequencing data sets.

The B-cell receptor (BCR) is essential for B-cell development and a crucial clinical target in immuno-oncology. However, therapeutic success against the BCR and downstream signaling pathways is hampered by enhanced NF-κB activation as a resistance mechanism. Using a multiomic approach, we discover the c-REL proto-oncogenic subunit of the NF-κB family as a key transcription factor regulating BCR subunit levels in B-cell lymphoma. Subsequent ChIP- seq, cell biology experiments, and patient data analysis reveal that OTUD4 is a critical deubiquitinase for inhibiting proteasomal degradation of c-REL and for stabilizing a multi-loop positive feedback of NF-κB to the BCR pathway. Remarkably, OTUD4 downregulation destabilizes c-REL and BCR levels and inhibits cell growth of B cell lymphoma. Thus, we shed light on the malignant potential of c-REL abundance, identify a positive feedback from c-REL to upstream BCR and present OTUD4 as a vulnerability to synergistically target NF-κB and BCR pathways in B-cell lymphoid malignancies.

/pdf/nf-kb-c-rel-otud4-axis-regulates-b-cell-receptor-in-b-cell-1pgsf819.pdf

NF-κB c-REL-OTUD4 axis regulates B-cell receptor in B-cell lymphoma

Conventional live-cell optical microscopy lacks sensitivity and specificity for label-free detection of intracellular protein-structure dynamics, such as conformational transition from α-helix to β-sheet. Detecting intermolecular β-sheet formation, for instance, is important because it is a hallmark of misfolded proteins and aggresome formation—which are intrinsic indicators of cell apoptosis in myeloma therapy. Going beyond conventional optical microscopy, we introduce a single-cell imaging technology with label-free sensitivity to intracellular intermolecular β-sheet formation in living cells. This unique ability was attained by exploiting the spectral specificity of the mid-infrared amide I region (1700 – 1600 cm-1) to protein structure and the positive-contrast nature of optoacoustic microscopy. By means of this technology, we were able to monitor the efficiency of proteasome inhibition in a myeloma cell line and—as a first demonstration towards clinical translation—in biopsied myeloma cells from patients. Achieving label-free monitoring of treatment at a single-cell level allows longitudinal assessment of response heterogeneity, which could provide crucial therapeutic information, such as patient-specific sensitivity to treatment, thus facilitating personalized medicine in myeloma therapy.

Protein-structure-sensitive mid-infrared optoacoustic microscopy enables label-free assessment of drug therapy in myeloma cells

Label-free assessment to myeloma therapy by protein structure sensitive mid-infrared optoacoustic microscopy

Single-nucleotide polymorphisms and locus amplification link the NF-κB transcription factor c-Rel to human autoimmune diseases and B cell lymphomas, respectively. However, the functional consequences of enhanced c-Rel levels remain enigmatic. Here, we overexpressed c-Rel specifically in mouse B cells from BAC-transgenic gene loci and demonstrate that c-Rel protein levels linearly dictated expansion of germinal center B (GCB) cells and isotype-switched plasma cells. c-Rel expression in B cells of otherwise c-Rel-deficient mice fully rescued terminal B cell differentiation, underscoring its critical B cell-intrinsic roles. Unexpectedly, in GCB cells transcription-independent regulation produced the highest c-Rel protein levels among B cell subsets. In c-Rel-overexpressing GCB cells this caused enhanced nuclear translocation, a profoundly altered transcriptional program, and increased proliferation. Finally, we provide a link between c-Rel gain and autoimmunity by showing that c-Rel overexpression in B cells caused autoantibody production and renal immune complex deposition.

/pdf/c-rel-gain-in-b-cells-drives-germinal-center-reactions-and-50xnf2w3hf.pdf

c-Rel gain in B cells drives germinal center reactions and autoantibody production

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NF-κB c-REL-OTUD4 axis regulates B-cell receptor in B-cell lymphoma

Protein-structure-sensitive mid-infrared optoacoustic microscopy enables label-free assessment of drug therapy in myeloma cells

Label-free assessment to myeloma therapy by protein structure sensitive mid-infrared optoacoustic microscopy

c-Rel gain in B cells drives germinal center reactions and autoantibody production