Aberrant NF-κB signaling in lymphoma:: mechanisms, consequences, and therapeutic implications

The transcription factor NF-kappa B is a tightly regulated positive mediator of T- and B-cell development, proliferation, and survival. The controlled activity of NF-kappa B is required for the coordination of physiologic immune responses. However, constitutive NF-kappa B activation can promote continuous lymphocyte proliferation and survival and has recently been recognized as a critical pathogenetic factor in lymphoma. Various molecular events lead deregulation of NF-kappa B signaling in Hodgkin disease and a variety of T- and B-cell non-Hodgkin lymphomas either upstream or downstream of the central I kappa B kinase. These alterations are prerequisites for lymphoma cell cycling and blockage of apoptosis. This review provides an overview of the NF-kappa B pathway and discusses the mechanisms of NF-kappa B deregulation in distinct lymphoma entities with defined aberrant pathways: Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), mucosa-associated lymphoid tissue (MALT) lymphoma, primary effusion lymphoma (PEL), and adult T-cell lymphoma/leukemia (ATL). In addition, we summarize recent data that validates the NF-kappa B signaling pathway as an attractive therapeutic target in T- and B-cell malignancies.