Classical and Alternative NF-.KAPPA.B Activation Pathways and Their Roles in Lymphoid Malignancies

Nuclear factor-κB (NF-κB) is a family of highly regulated dimeric transcription factors that play pivotal roles in inflammatory responses and immunological reactions. Although they are often activated concurrently, classical and alternative NF-κB activation pathways have distinct regulatory functions, producing secondary inflammatory responses and regulating lymphoid organ development, respectively. As NF-κB functions in the proliferation, differentiation, and survival of lymphocytes, increased activation also participates in the oncogenesis of many lymphoid malignancies. Aberrant NF-κB activation in these tumor cells results from genetic changes or the activation of NF-κB pathways by indirect mechanisms. Recent observations have suggested that NF-κB provides many of the requirements for cellular transformation. Bcl-3, a member of the IκB family, is overexpressed in t (2 ; 5)+ anaplastic large cell lymphoma due to genetic and epigenetic alterations. The different contributions of the classical and alternative NF-κB pathways to tumorigenesis, however, are not well understood. The clinical importance of NF-κB is also being recognized, with the approval of the NF-κB inhibitor bortezomib for treatment of advanced multiple myeloma. A better understanding of the molecular pathways involving NF-κB will surely contribute to more sophisticatedly targeted treatments for malignancies in the future.