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Stroma-mediated dysregulation of myelopoiesis in mice lacking IkappaBalpha

Item Type:Article
Title:Stroma-mediated dysregulation of myelopoiesis in mice lacking IkappaBalpha
Creators Name:Rupec, R.A. and Jundt, F. and Rebholz, B. and Eckelt, B. and Weindl, G.N. and Herzinger, T. and Flaig, M.J. and Moosmann, S. and Plewig, G. and Doerken, B. and Foerster, I. and Huss, R. and Pfeffer, K.
Abstract: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 (ikbaflox/flox × LysM-Cre) and in fetal liver cell chimeras (ikbaFLΔ/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.
Keywords:Alleles, Calcium-Binding Proteins, Down-Regulation, Gene Deletion, Gene Expression Regulation, Hematopoietic System, I-kappa B Proteins, Intercellular Signaling Peptides and Proteins, Liver, Membrane Proteins, Myelopoiesis, Myeloproliferative Disorders, Proteins, Signal Transduction, Stromal Cells, Animals, Mice
Page Range:479-491
Date:1 January 2005
Official Publication:https://doi.org/10.1016/j.immuni.2005.02.009
PubMed:View item in PubMed

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