NF-κB fingerprinting reveals heterogeneous NF-κB composition in diffuse large B-cell lymphoma

Abstract

IntroductionImproving treatments for Diffuse Large B-Cell Lymphoma (DLBCL) is challenged by the vast heterogeneity of the disease. Nuclear factor-κB (NF-κB) is frequently aberrantly activated in DLBCL. Transcriptionally active NF-κB is a dimer containing either RelA, RelB or cRel, but the variability in the composition of NF-κB between and within DLBCL cell populations is not known.ResultsHere we describe a new flow cytometry-based analysis technique termed “NF-κB fingerprinting” and demonstrate its applicability to DLBCL cell lines, DLBCL core-needle biopsy samples, and healthy donor blood samples. We find each of these cell populations has a unique NF-κB fingerprint and that widely used cell-of-origin classifications are inadequate to capture NF-κB heterogeneity in DLBCL. Computational modeling predicts that RelA is a key determinant of response to microenvironmental stimuli, and we experimentally identify substantial variability in RelA between and within ABC-DLBCL cell lines. We find that when we incorporate NF-κB fingerprints and mutational information into computational models we can predict how heterogeneous DLBCL cell populations respond to microenvironmental stimuli, and we validate these predictions experimentally.DiscussionOur results show that the composition of NF-κB is highly heterogeneous in DLBCL and predictive of how DLBCL cells will respond to microenvironmental stimuli. We find that commonly occurring mutations in the NF-κB signaling pathway reduce DLBCL’s response to microenvironmental stimuli. NF-κB fingerprinting is a widely applicable analysis technique to quantify NF-κB heterogeneity in B cell malignancies that reveals functionally significant differences in NF-κB composition within and between cell populations.

Oncogenic Ras-driven Dorsal/NF-κB signaling contributes to tumorigenesis in aDrosophilacarcinoma model

“…While NF-kB protein heterogeneity within the same tumour has not been studied yet in solid mammal tumours, the NF-kB fingerprinting and their subsequent homo-/heterodimerization within diffuse large B-cell lymphoma hold predictive values for the tumour cell response to microenvironmental activating cues [47]. With our study, this finding, suggest that NF-kB composition heterogeneity might also occur in solid mammal cancers and modulate their response to microenvironmental inflammation.…”

Anomaly Detection and Artificial Intelligence Identified the Pathogenic Role of Apoptosis and RELB Proto-Oncogene, NF-kB Subunit in Diffuse Large B-Cell Lymphoma

“…This is a relevant result because immuno-oncology and immunotherapeutic therapies in DLBCL include monoclonal anti-CD20 antibody (rituximab), monoclonal anti-PD-1 antibodies (nivolumab and pembrolizumab), monoclonal anti-PD-L1 antibodies (avelumab, durvalumab, and atezolizumab), and chimeric antigen receptor (CAR) T-cell therapy [121,122]. The role of RELB in the pathogenesis of DLBCL is complex [103,104,118,[123][124][125][126]. Further analysis of the impact of RELB on the prognosis of DLBCL and their relationship with known and well stablished markers such as MYC, BCL2, and BCL6 [12,127] is warranted.…”

Research Progress Regarding the Effect and Mechanism of Dietary Polyphenols in Liver Fibrosis

“…The NF-κB family of transcription activators includes RelA, RelB, and cRel, and two family members (p50 and p52) forming heterodimers with transcriptional active proteins. Additionally, these simulations predicted that increased RelA activity might decrease cRel activity by competing for p50 [115,116]. These transcription factors may regulate inflammation and apoptosis primarily through the NF-κB/IκBα signaling pathway [117].…”