Classical and Alternative NF-kB Activation Pathways and Their Roles in Lymphoid Malignancies

Nuclear factor-kB (NF-kB) 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-kB activation pathways have distinct regulatory functions, producing secondary inflammatory responses and regulating lymphoid organ development, respectively. As NF-kB functions in the proliferation, differentiation, and survival of lymphocytes, increased activation also participates in the oncogenesis of many lymphoid malignancies. Aberrant NF-kB activation in these tumor cells results from genetic changes or the activation of NF-kB pathways by indirect mechanisms. Recent observations have suggested that NF-kB provides many of the requirements for cellular transformation. Bcl-3, a member of the IkB 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-kB pathways to tumorigenesis, however, are not well understood. The clinical importance of NF-kB is also being recognized, with the approval of the NF-kB inhibitor bortezomib for treatment of advanced multiple myeloma. A better understanding of the molecular pathways involving NF-kB will surely contribute to more sophisticatedly targeted treatments for malignancies in the future.