NF-kappaB is dispensable for normal lymphocyte development in bone marrow but required for protection of progenitors...

Levels of the nuclear factor-kappa B (NF-kappaB)/Rel family of proteins are carefully modulated in differentiating lymphocytes, where these transcription factors are thought to be important for survival and fate decisions. In contrast, gene-targeting experiments have not revealed clear roles for these transcription factors in lymphopoiesis within bone marrow. Inhibition of NF-kappaB by introduction of mutated I kappa B alpha, a 'superinhibitor' of NF-kappaB, into hematopoietic stem cells or early progenitors suppressed B as well as T lymphopoiesis following transplantation into immunodeficient mice. Furthermore, a NF-kappaB essential modifier-binding domain (NBD) peptide that blocks IKB kinase (IKK) activity selectively impaired the generation of adult B lineage cells. However, this suppression did not occur when a neutralizing antibody to tumor necrosis factor alpha (TNFalpha) was added to the cultures, or in circumstances where few non-lymphoid cells were present. We conclude that while NF-kappaB plays a survival-promoting role in lymphoid progenitors, this may only be significant in circumstances such as transplantation when levels of TNFalpha are high.