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The genetic programs that maintain hematopoiesis during steady state in physiologic conditions are different from those activated during stress. Here, we show that hematopoietic stem cells (HSCs) with deficiencies in components of the alternative NFκB pathway (the NFκB inducing kinase, NIK, and the downstream molecule NFκB2) had a defect in response to stressors such as supraphysiological doses of cytokines, chemotherapy, and hematopoietic transplantation. NIK‐deficient mice had peripheral blood and bone marrow leukocyte numbers within normal ranges (except for the already reported defects in B‐cell maturation); however, HSCs showed significantly slower expansion capacity in in vitro cultures compared to wild‐type HSCs. This was due to a delayed cell cycle and increased apoptosis. In vivo experiments showed that NIK‐deficient HSCs did not recover at the same pace as controls when challenged with myeloablative chemotherapy. Finally, NIK‐deficient HSCs showed a significantly decreased competitive repopulation capacity in vivo. Using HSCs from mice deficient in one of two downstream targets of NIK, that is, either NFκB2 or c‐Rel, only NFκB2 deficiency recapitulated the defects detected with NIK‐deficient HSCs. Our results underscore the role of NIK and the alternative NFκB pathway for the recovery of normal levels of hematopoiesis after stress. S tem  C ells   2015;33:2825–2837

The NFKB Inducing Kinase Modulates Hematopoiesis During Stress