In this issue of Blood, the noncanonical NF-kappaB pathway and/or the canonical pathway, is aberrantly activated in 17% of patients with MM and 40% of MM cell lines through various gene abnormalities that result in NIK stabilization mostly. The NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway involves dimers of transcription factors (TFs) of the Rel/NF-KB family, comprising RelA/P65, c-rel, RelB, NF-kappaB1 (p50 and its pl05 precursor) and NK-kappaB2 (p52 and its precursor p 100). NF-kappaB pathway plays a central role in infection and inflammation, and in lymphopoiesis, particularly in normal B-cell and plasma cell development. These TFs are normally kept inactive in the cytoplasm through binding with inhibitors called IkappaB (inhibitor of kappaB) or unprocessed NF-kappaB1 or NF-kappaB2. Cell activation may result in activation of IkB kinases (IKKs), mainly IKKbeta in the canonical pathway and IKKalpha in the non-canonical pathway. Activation of IKKbeta results in the phosphorylation, ubiquitination, and degradation of IkappaBalpha and other IkappaBs, releasing TF dimers (mainly P65/P50) to the nucleus that activate NF-kappaB target genes.
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