Aberrant NF-κB signaling in lymphoma: mechanisms, consequences, and therapeutic implications

Abstract

IntroductionThe development, maintenance, and progression of malignant lymphomas depend mechanistically on a deregulation of cellular pathways that control differentiation, proliferation, or apoptosis in lymphocytes. One essential and tightly regulated signaling cascade that mediates development, activation, and survival of normal lymphocytes for regulated immune responses is the nuclear factor-B (NF-B) pathway. In recent years it is becoming clear that aberrant deregulated NF-B activation is a hallmark of several lymphoid malignancies and is directly linked to advanced disease. Several lymphoma types depend on NF-B activity for cell cycling and survival, indicating that an inhibition of this pathway could be a therapeutic option. Here, we review the central components and the molecular regulation of NF-B signaling as well as summarize mechanisms and consequences of aberrant NF-B activation in distinct lymphoma entities, together with experimental data that validate the NF-B pathway as a therapeutic target in lymphoma. Physiology of NF-B signaling Mechanisms of NF-B activationNF-B is not a single protein, but a small family of inducible transcription factors that operates in virtually all mammalian cells. 1 It plays a particular important role in the activation and survival of immune cells. 2 The 5 mammalian NF-B/Rel members are RelA (p65), RelB, c-Rel, NF-B1 (p50 and its precursor p105), and NF-B2 (p52 and its precursor p100) ( Figure 1A). These proteins form various homodimers and heterodimers and are kept inactive by cytoplasmic association with inhibitory proteins, which consist of IB␣, IB␤, IB⑀, as well as the p105 and p100 precursors of p50 and p52, respectively ( Figure 1B). Physiologic activation of NF-B occurs mainly through either the canonical or the alternative pathway ( Figure 2). 2 Both pathways are based on inducible phosphorylation of IB proteins by the multiprotein IB-kinase (IKK) that contains 2 catalytic subunits, IKK␣ (IKK1) and IKK␤ (IKK2), as well as the regulatory subunit IKK␥ (or NEMO for NF-B essential modifier) ( Figure 1C).The canonical pathway of NF-B activation can be engaged by a large series of stimuli, including proinflammatory cytokines, pathogen-associated molecular patterns that bind to innate immune receptors, T-cell receptor (TCR) and B-cell receptor (BCR) signaling, as well as ligation of lymphocyte coreceptors. 1-3 Activated IKK phosphorylates IB proteins, thereby inducing IB polyubiquitinylation and subsequent proteolytic degradation by the proteasome. Following IB degradation, NF-B dimers are released and are then able to translocate into the nucleus, activating gene transcription ( Figure 2A).The alternative pathway of NF-B activation represents an additional specialized signaling cascade that is particularly important in mature B cells. This pathway is engaged by a restricted set of cell-surface receptors that belong to the TNF receptor superfamily, including CD40, the lymphotoxin ␤ receptor, and BAFF receptor. 2 This pathway culminates in the activation of IKK␣ that di...

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