Constitutive activation of NF-κB during early bone marrow development results in loss of B cells at the pro-B-cell stage

There is a considerable body of work exploring the role of NF-kappa B family of transcription factors in the maturation and functions of later stage B cells; however, their role in the earlier bone marrow stages of development is less well understood despite the demonstration that NF-kappa B activity is present at all early stages of B-cell development. To explore the consequences of early, B cell-targeted constitutive activation of both NF-kappa B pathways on B-cell development, we generated mice that have either or both. NF-kappa B pathways constitutively activated beginning in early pro-B cells. In marked contrast to activating a single pathway, we found mice with both pathways constitutively activated displayed a profound loss of B cells, starting with early pro-B cells and peaking at the late pro-B-cell stage, at least in part as a result of increased apoptosis. This effect was found to be cell autonomous and to have striking phenotypic consequences on the secondary lymphoid organs and circulating antibody levels. This effect was also found to be temporal in nature as similar activation under a Cre expressed later in development did not result in generation of a similar phenotype. Taken together, these findings help to shed further light on the need for tight regulation of the NF-kappa B family of transcription factors during the various stages of B-cell development in the bone marrow.