Nuclear factor-kappaB modulation as a therapeutic approach in hematologic malignancies

Nuclear factor-kappaB (NF-kappaB) is a collective term that refers to a small class of dimeric transcription factors for a number of genes, including growth factors, angiogenesis modulators, cell-adhesion molecules, and antiapoptotic factors. Although most NF-kappaB proteins promote transcription, some act as inactivating or repressive complexes. The most common p50-RelA (p65) dimer known "specifically" as NF-kappaB, is relatively abundant, controls the expression of numerous genes, and exists as an inactive cytoplasmic complex bound to inhibitory proteins of the NF-kappaB inhibitor (IkappaB) family. The inactive NF-kappaB-IkappaB complex is activated by a variety of stimuli, including proinflammatory cytokines, mitogens, growth factors, and stress-inducing agents. The release of NF-kappaB facilitates its translocation to the nucleus, where it promotes cell survival by initiating the transcription of genes encoding stress-response enzymes, cell-adhesion molecules, proinflammatory cytokines, and antiapoptotic proteins. Constitutive activation of NF-kappaB in the nucleus is observed in some hematologic disorders. With the recent approval of bortezomib for patients with advanced multiple myeloma, NF-kappaB modulation is likely to be a therapeutic endeavor of increasing interest in coming years.