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In the complex microenvironment where they evolve, developing cells undergo rapid programmed cell death (PCD) when cytokines that support them become limiting. The transcriptional mechanisms of cytokine-withdrawal apoptosis are poorly understood. In this report, we used early B-lymphocyte tissue culture and transgenic cells to demonstrate that nuclear factor-kappaB (NF-kappaB) promotes apoptosis during cytokine withdrawal-induced PCD. In the progenitor B lymphocyte model FL5.12, whereas NF-kappaB has an antiapoptotic function in response to tumor necrosis factor-alpha, cytokine withdrawal causes nuclear translocation of NF-kappaB/cRel, where it is apoptogenic. Inhibition of NF-kappaB activation delays cytokine withdrawal-induced PCD in both FL5.12 and transgenic early B cells. Additionally, reconstituting a bone marrow microenvironment ex vivo abrogates the differential apoptotic pattern between control and transgenic early B cells.