Hematopoiesis occurs in the liver and the bone marrow (BM) during murine development. Newborn mice with a ubiquitous deletion of IκBα develop a severe hematological disorder characterized by an increase of granulocyte/erythroid/monocyte/macrophage colony-forming units (CFU-GEMM) and hypergranulopoiesis. Here, we report that this particular myeloproliferative disturbance is mediated by continuously deregulated perinatal expression of Jagged1 in IκBα-deficient hepatocytes. The result is a permanent activation of Notch1 in neutrophils. In contrast, in mice with a conditional deletion of IκBα only in the myeloid lineage (ikba^flox/flox × LysM-Cre) and in fetal liver cell chimeras (ikba^FLΔ/FLΔ), a cell-autonomous induction of the myeloproliferative disease was not observed. Coculture of IκBα-deficient hepatocytes with wild-type (wt) BM cells induced a Jagged1-dependent increase in CFUs. In summary, we show that cell-fate decisions leading to a premalignant hematopoietic disorder can be initiated by nonhematopoietic cells with inactive IκBα.