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Review
. 2022 Sep 1;10(9):2153.
doi: 10.3390/biomedicines10092153.

NFkB Pathway and Hodgkin Lymphoma

Fabrice Jardin  1
Affiliations
Review

NFkB Pathway and Hodgkin Lymphoma

Fabrice Jardin. Biomedicines. .

Abstract

The tumor cells that drive classical Hodgkin lymphoma (cHL), namely, Hodgkin and Reed-Sternberg (HRS) cells, display hallmark features that include their rareness in contrast with an extensive and rich reactive microenvironment, their loss of B-cell phenotype markers, their immune escape capacity, and the activation of several key biological pathways, including the constitutive activation of the NFkB pathway. Both canonical and alternative pathways are deregulated by genetic alterations of their components or regulators, EBV infection and interaction with the microenvironment through multiple receptors, including CD30, CD40, BAFF, RANK and BCMA. Therefore, NFkB target genes are involved in apoptosis, cell proliferation, JAK/STAT pathway activation, B-cell marker expression loss, cellular interaction and a positive NFkB feedback loop. Targeting this complex pathway directly (NIK inhibitors) or indirectly (PIM, BTK or NOTCH) remains a challenge with potential therapeutic relevance. Nodular predominant HL (NLPHL), a distinct and rare HL subtype, shows a strong NFkB activity signature because of mechanisms that differ from those observed in cHL, which is discussed in this review.

Keywords: Hodgkin lymphoma; NFkB pathway; cfDNA; targeted therapy.

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Conflict of interest statement

The author declares no conflict of Interest.

Figures

Figure 1
Figure 1
Schematic physiopathological model of classical Hodgkin lymphoma and its relationship with the NFkB pathway. The tumor cells that drive classical Hodgkin lymphoma (cHL) are Hodgkin and Reed-Sternberg (HRS) cells. These B cells are isolated from the germinal center and are rescued from apoptosis despite unproductive or crippled IgV by mechanisms that involve Epstein Barr virus (EBV) or NFkB deregulation. Interaction with the microenvironment, including mainly T cells but also mastocytes, macrophages, and myeloid cells, creates an interaction that favors HRS cell survival. The NFkB pathway is deregulated by multiple mechanisms, including NFkB signaling activation through genetic lesions, interaction with microenvironment cells, and TNF receptor activation or EBV activation. The deregulation of the NFkB pathway is involved in the transcriptional control of several target genes involved in apoptosis, the JAK/STAT pathway, B-cell marker expression loss, microenvironment crosstalk, or cell proliferation. Figure generated using Servier Medical Art and personal archive PET scan imaging.
Figure 2
Figure 2
Schematic view of the involvement of the canonical and alternative NFkB pathways in classical Hodgkin lymphoma pathogenesis. The canonical and noncanonical NF-KB pathways are activated in HRS cells by several TNF receptors, except BCR, BAFF-R, and LTB-R, which are not expressed by these cells. CD30, CD40, and LMP1 are able to activate both alternative and canonical pathways. Following receptor activation, TNF receptor-associated factors (TRAFs) interact with the IKK complex or NIK in the canonical and alternative pathways, respectively. This activation leads to the ubiquitination of the inhibitors IKBα and IKBε and their destruction by the proteasome. Transcription factor heterodimers (p50-p65, p52-RelB, p50-p50) are then released and translocated to the nucleus to regulate NFkB target genes (including genes positively or negatively regulated). Negative (A20, CYLD, TRAF3, and IKBα/ε) and positive regulators (Rel, MAP3K14, and BCL3) of the pathways can be targeted by genetic alterations (*/**) in 50% of cHL cases. BCR, BAFF-R and LTβR receptors are usually not expressed by HRS cells. Figure build using Servier Medical Art.
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Grants and funding

This research received no external funding.