Abstract
The NF-κB transcription factor family plays a crucial role in lymphocyte proliferation and survival. Consequently, aberrant NF-κB activation has been described in a variety of lymphoid malignancies, including diffuse large B-cell lymphoma, Hodgkin lymphoma, and adult T-cell leukemia. Several factors, such as persistent infections (e.g., with Helicobacter pylori), the pro-inflammatory microenvironment of the cancer, self-reactive immune receptors as well as genetic lesions altering the function of key signaling effectors, contribute to constitutive NF-κB activity in these malignancies. In this review, we will discuss the molecular consequences of recurrent genetic lesions affecting key regulators of NF-κB signaling. We will particularly focus on the oncogenic mechanisms by which these alterations drive deregulated NF-κB activity and thus promote the growth and survival of the malignant cells. As the concept of a targeted therapy based on the mutational status of the malignancy has been supported by several recent preclinical and clinical studies, further insight in the function of NF-κB modulators and in the molecular mechanisms governing aberrant NF-κB activation observed in lymphoid malignancies might lead to the development of additional treatment strategies and thus improve lymphoma therapy.
Highlights
The NF-κB transcription factor family plays a crucial role in lymphocyte proliferation and survival
Expression of a non-functional variant of Unc93b1, which is required for the endolysosomal localization of TLR3, 7, and 9, as well as TLR9 deficiency block the proliferation of primary B cells induced by the expression of ectopic MyD88L265P in vitro, implicating a continued dependence on upstream TLR9 activation [52]
Stimulus-dependent activation of the IKK complex results in the phosphorylation and subsequent proteasomal degradation of IκBα and IκBε. This allows the nuclear translocation of transcriptionally active RelA/p50 or c-Rel/p50 heterodimers; (b) Genetic alterations resulting in the expression of non-functional truncated versions of IκBα and IκBε, which lack part of the ankyrin repeat domain and are unable to bind to the NF-κB transcription factors, promote constitutive NF-κB
Summary
The NF-κB transcription factors are involved in the regulation of a variety of biological processes, such as inflammation, survival, and proliferation. NF-κB activation in response to extracellular cues is regulated by two distinct pathways: In the canonical NF-κB pathway, stimulus-dependent activation of the IκB kinase (IKK) complex, comprising the catalytic subunits IKKα and IKKβ as well as the regulatory subunit IKKγ ( known as NF-κB essential modulator; NEMO), results in the phosphorylation and subsequent proteasomal degradation of the IκB proteins [1,2]. This allows the nuclear translocation of the NF-κB transcription factors, preferentially heterodimers of p50 and RelA or c-Rel, as well as their subsequent DNA binding and target gene transcription. The exact molecular characterization of the key oncogenic mechanisms of constitutive NF-κB activation either shared by several or unique to certain lymphoid malignancies might allow the rational design of therapeutic strategies tailored to the specific tumor entities and might significantly improve lymphoma therapy
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