Stroma-Mediated Dysregulation of Myelopoiesis in Mice Lacking IκBα

Abstract

Hematopoiesis occurs in the liver and the bone marrow (BM) during murine development. Newborn mice with a ubiquitous deletion of I kappa B alpha 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 I kappa B alpha-deficient hepatocytes. The result is a permanent activation of Notch1 in neutrophils. In contrast, in mice with a conditional deletion of I kappa B alpha only in the myeloid lineage (ikba(flox/flox) x LysM-Cre) and in fetal liver cell chimeras (ikba(FL delta/FL delta)), a cell-autonomous induction of the myeloproliferative disease was not observed. Coculture of I kappa B alpha-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 I kappa B alpha.

Unravelling the complexities of the NF-κB signalling pathway using mouse knockout and transgenic models

“…Whereas deregulated expression of inflammatory mediators enhances the recruitment and prolongs the survival of neutrophils, the presence of increased numbers of myeloid progenitors in ikba À/À mice indicates that granulopoiesis may also be deregulated. Using radiation chimeras reconstituted with fetal liver hemopoietic progenitors, coupled with the conditional removal of IkBa in the hemopoietic compartment, the myeloproliferative phenotype seen in ikba À/À mice was determined not to be myeloid cell autonomous (Rupec et al, 2005). Instead, the expansion of myeloid progenitors was driven by the continuous deregulated perinatal expression of the NF-kB-dependent target gene Jagged-1 in ikba À/À hepatocytes, a finding that indicates that myeloid hyperplasia can be initiated by constitutive NF-kB signals in non-hematopoietic cells.…”

IκBα is required for marginal zone B cell lineage development

“…To generate mice with tissue-specific deletion of IjBa, loxP sites were introduced into the IjBa locus of mouse embryonic stem (ES) cells by homologous recombination as previously described [25]. To selectively disrupt the IjBa gene in B cells, IjBa f/f mice were crossed with CD19-Cre mice, which induced efficient B lineagespecific deletion of the loxP-flanked target sequence.…”

“…IjBa cKO mice were generated as previously described [25]. Mice were genotyped by PCR using the following primers: lox1 5 0 -gtggagtcagatgtagcac-3 0 and lox2 5 0 -agaaagggataagccatgga-3 0 .…”

“…For detection of the floxed and deleted Ikba allele, DNA isolated from the indicated tissues was digested with KpnI and hybridized with a 32 P-labeled 3 0 -flanking probe as described previously [25].…”

Bone Marrow Microenvironment in the Pathogenesis of AML

“…These results suggest that PTEN deficiency in HSC alone is not sufficient for malignant transformation. Rupec et al (2005) reported that activation of NF-kB in myelopoietic cells and the absence of its inhibitor IκBα are not sufficient for induction of hypergranulopoiesis, but these changes in the non-hematopoietic compartment, such as fetal liver, resulted in increased numbers of dysplastic hematopoietic cells with progression into secondary AML. These results indicate that non-hematopoietic cells with inactive IκBα can initiate premalignant hematopoietic disorder, conceivably via activation of the Notch pathway.…”