NF-κB signaling and its relevance to the treatment of mantle cell lymphoma

Abstract

Mantle cell lymphoma is an aggressive subtype of non-Hodgkin B cell lymphoma that is characterized by a poor prognosis determined by Ki67 and Mantle Cell International Prognostic Index scores, but it is becoming increasingly treatable. The majority of patients, especially if young, achieve a progression-free survival of at least 5 years. Mantle cell lymphoma can initially be treated with an anti-CD20 antibody in combination with a chemotherapy backbone, such as VR-CAP (the anti-CD20 monoclonal antibody rituximab administered with cyclophosphamide, doxorubicin, and prednisone) or R-CHOP (the anti-CD20 monoclonal antibody rituximab administered with cyclophosphamide, doxorubicin, vincristine, and prednisone). While initial treatment can facilitate recovery and complete remission in a few patients, many patients experience relapsed or refractory mantle cell lymphoma within 2 to 3 years after initial treatment. Targeted agents such as ibrutinib, an inhibitor of Bruton's tyrosine kinase, which has been approved only in the relapsed setting, can be used to treat patients with relapsed or refractory mantle cell lymphoma. However, mantle cell lymphoma cells often acquire resistance to such targeted agents and continue to survive by activating alternate signaling pathways such as the PI3K-Akt pathway or the NF-κB pathways.NF-κB is a transcription factor family that regulates the growth and survival of B cells; mantle cell lymphoma cells depend on NF-κB signaling for continued growth and proliferation. The NF-κB signaling pathways are categorized into canonical and non-canonical types, wherein the canonical pathway prompts inflammatory responses, immune regulation, and cell proliferation, while the non-canonical leads to B cell maturation and lymphoid organogenesis. Since these pathways upregulate survival genes and tumor-promoting cytokines, they can be activated to overcome the inhibitory effects of targeted agents, thereby having profound effects on tumorigenesis. The NF-κB pathways are also highly targetable in that they are interconnected with numerous other pathways, including B cell receptor signaling, PI3K/Akt/mTOR signaling, and toll-like receptor signaling pathways. Additionally, elements of the non-canonical NF- κB pathway, such as NF-κB-inducing kinase, can be targeted to overcome resistance to targeting of the canonical NF- κB pathway.Targeting the molecular mechanisms of the NF-κB pathways can facilitate the development of novel agents to treat malignancies and overcome drug resistance in patients with relapsed or refractory mantle cell lymphoma.

Keywords: Canonical pathway; Mantle cell lymphoma; NF-κB; Non-canonical pathway.

Fig. 1

B cell receptor signaling pathway with receptors, inhibitors, targets, and other molecules. B cell receptor signaling mediates the canonical pathway for nuclear translocation of the transcription factor NF-κB. Initial activation of the B cell receptor activates Src family kinases and the Syk and Btk tyrosine kinases, which form a signalosome complex with other signaling enzymes and proteins. Btk phosphorylates and activates PLCγ2, which yields the downstream molecules inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG) and sensitizes PKCβ due to release of calcium ions. The activated PKC leads to formation of the CBM complex; the IKK complex is then activated, which phosphorylates IκB, allowing it to be ubiquitinated and proteasomally degraded. The p50 and p65-RelA NF-κB heterodimer is then released into the nucleus to induce gene expression

Fig. 2

NF-κB signaling pathways with receptors, inhibitors, targets, and other molecules The canonical and non-canonical pathways for NF-κB signaling are mediated by various receptors and signaling molecules, including toll-like receptors (TLR), tumor necrosis factor receptors (TNFR), interleukin-1 receptor (IL-1R), CD40, initiation of B cell activation factor (BAFFR), lymphotoxin β- receptor (LTβR), and receptor activator for nuclear factor kappa B (RANK). The canonical NF-κB pathway involves the inhibition of NF-κB by IκB, which binds to the p50–p65 heterodimer in the cytoplasm and prevents it from entering the nucleus. Activation of BCR, TNFR, and IL-1R receptors initiates adapter protein and signaling kinase responses, leading to activation of the IκB kinase (IKK) complex. Kinases in the IKK complex phosphorylate IκB and lead to its poly-ubiquitination and proteasomal degradation. This allows the p50 and p65-RelA heterodimer (a complex from the NF-κB family) to be released into the nucleus to induce gene expression. In the non-canonical pathway, IKKα is activated by the upstream kinase NF-κB-inducing kinase (NIK), which promotes the processing of p100 into the active RelB-p52 isoform of NF-κB. NIK is downregulated by the expression of TRAF2 and TRAF3, which are negative regulators of non-canonical NF-κB signaling that interact with BIRC2 and BIRC3 [1]. Unlike the canonical pathway, the non-canonical pathway does not rely on IKKβ or IKKγ (NEMO); it only needs IKKα to phosphorylate the p52 precursor, p100