The NF- B Activating Pathways in Multiple Myeloma

Abstract

Multiple myeloma(MM), an incurable plasma cell cancer, represents the second most prevalent hematological malignancy. Deregulated activity of the nuclear factor kappaB (NF- B) 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- B system in myeloma cells. In fact, frequent engagement of both the NF- B pathways constitutes a distinguishing characteristic of myeloma. In turn, NF- B signaling promotes proliferation, survival and drug-resistance of myeloma cells. In this review article, we catalog NF- B 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- B -driven gene-expressions in healthy and malignant cells. Furthermore, we discuss signaling crosstalk between concomitantly triggered NF- B pathways, and its plausible implication for anomalous NF- B activation and NF- B driven pro-survival gene-expressions in multiple myeloma. Finally, we propose that mechanistic understanding of NF- B deregulations may provide for improved therapeutic and prognostic tools in multiple myeloma.