Abstract
Multiple myeloma(MM), an incurable plasma cell cancer, represents the second most prevalent hematological malignancy. Deregulated activity of the nuclear factor kappaB (NF-κB) family of transcription factors has been implicated in the pathogenesis of multiple myeloma. Tumor microenvironment-derived cytokines and cancer-associated genetic mutations signal through the canonical as well as the non-canonical arms to activate the NF-κB system in myeloma cells. In fact, frequent engagement of both the NF-κB pathways constitutes a distinguishing characteristic of myeloma. In turn, NF-κB signaling promotes proliferation, survival and drug-resistance of myeloma cells. In this review article, we catalog NF-κB activating genetic mutations and microenvironmental cues associated with multiple myeloma. We then describe how the individual canonical and non-canonical pathways transduce signals and contribute towards NF-κB -driven gene-expressions in healthy and malignant cells. Furthermore, we discuss signaling crosstalk between concomitantly triggered NF-κB pathways, and its plausible implication for anomalous NF-κB activation and NF-κB driven pro-survival gene-expressions in multiple myeloma. Finally, we propose that mechanistic understanding of NF-κB deregulations may provide for improved therapeutic and prognostic tools in multiple myeloma.
Highlights
Multiple myeloma(MM), an incurable plasma cell cancer, represents the second most prevalent hematological malignancy
We have focused on NF-κB deregulations in MM; for a more comprehensive description of MM and the underlying genetic as well as cell-signaling anomalies, please see [4,32]
It will be important to investigate further if we propose that dysfunctions of an integrated NF-κB system, and not that of the individual ongoing canonical signaling reinforces the RelB NF-κB activity induced by the non-canonical canonical and non-canonical pathways, cause pathological NF-κB activity in MM
Summary
Heterogeneous cancer-associated mutations often influence the interaction of malignant cells with their microenvironment that modifies therapeutic outcomes. Immune cells as well as stromal cells secrete a diverse array of pro-inflammatory cytokines, which activate key pro-survival signaling pathways in malignant cells. Sequencing of cancer genomes revealed recurrent gain-of-function mutations in genes encoding key positive regulators of NF-κB signaling and inactivating genetic aberrations in negative regulators of this pathway. Multiple myeloma (MM), a plasma cell malignancy, provides one of the best examples where a number of mutations have been mapped onto the NF-κB pathway. We discuss the NF-κB-activating genetic lesions associated with MM and the role of the tumor microenvironment in reinforcing NF-κB signaling in cancerous cells. We elaborate interdependent regulations of NF-κB-activating pathways in Biomedicines 2018, 6, 59
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