The Notch Ligand Jagged1 Causes a Myeloproliferative Disorder in Mice Lacking IκBα.

Hematopoiesis occurs in the liver and the bone marrow 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 provide evidence that this particular myeloproliferative disturbance is mediated by continuously deregulated perinatal expression of the Notch ligand Jagged1 in IκBα-deficient hepatocytes. Signaling through Notch-family cell surface receptors and their ligands has been shown to be involved in cell fate decisions of stem cells during hematopoietic/mesenchymal differentiation. However, the role of Notch signaling in myelopoiesis is still under discussion as results gained using different experimental conditions are contradictory. Due to embryonic lethality of Notch1- and Jagged1-deficient mice, alterations of myelopoiesis are difficult to be adressed. In this study, we investigated the function of IκBα and its role within the Jagged/Notch signaling pathway during myelopoiesis. Therefore, a novel mouse line with a conditional (floxed) allele of ikba was established. Ubiquitous deletion of IκBα after cross-breeding with Deleter-Cre mice results in hypergranulopoiesis comparable to the conventional deletion of the allele. A detailed analysis revealed a myeloproliferative syndrome with increased numbers of cycling progenitor cells. The morphological analysis of liver and bone marrow of IκBα-deficient mice showed hypercellularity. The cellular components were dominated by myeloid lineages and represented mostly granulocyts with dysplastic features, characterized by pseudo-Pelger-Huet formation. Myelodysplasia could also be detected in megakaryopoiesis by the presence of micromegakaryocytes. Alterations in erythropoiesis were detectable by condensed chromatin and an asychrony of the nucleocytoplasmic ratio in the red cell precursor population. Together, our results indicate that ubiquitous loss of IκBα results in hypergranulopoiesis progressing to a myelodysplastic syndrome. Systematic analysis of transcription factors, growth factor receptors and NF-κB-regulated cell-survival genes was performed to determine molecular mechanisms underlying hypergranulopoiesis. Our data suggested that Notch1-dependent signals were responsible for the myeloproliferative disorder as Notch1 was upregulated in neutrophils and the Notch ligand Jagged1 in non-hematopoietic cells, namly hepatocytes. Myeloproliferation could be inhibited by blocking the Notch1 ligand Jagged1. Interestingly, deletion of IκBα in neutrophils and macrophages or hematopoietic stem cells did not result in dysregulation of myelopoiesis despite constitutive NF-κB activation in these cells. This establishes the relevance of non-hematopoietic expression of Jagged1 for the control and regulation of myelopoiesis. In summary, we show that cell-fate decisions leading to a premalignant hematopoietic disorder can be initiated by non-hematopoietic cells with inactive IκBα.