Stroma-mediated dysregulation of myelopoiesis in mice lacking I kappa B alpha.
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.
Rupec
Rudolf A
RA
Department of Dermatology, University of Munich, Frauenlobstrasse 9-11, D-80337 Munich, Germany. rudolf.rupec@med.uni-muenchen.de
Jundt
Franziska
F
Rebholz
Bernd
B
Eckelt
Birgit
B
Weindl
Günther
G
Herzinger
Thomas
T
Flaig
Michael J
MJ
Moosmann
Sabine
S
Plewig
Gerd
G
Dörken
Bernd
B
Förster
Irmgard
I
Huss
Ralf
R
Pfeffer
Klaus
K
D000483:Alleles; D000818:Animals; D002135:Calcium-Binding Proteins; D015536:Down-Regulation; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006413:Hematopoietic System / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics* / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008099:Liver / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D008565:Membrane Proteins; D051379:Mice; D038042:Myelopoiesis / Q000235:genetics*; D009196:Myeloproliferative Disorders / Q000235:genetics*; D000072000:NF-KappaB Inhibitor alpha; D011506:Proteins / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology
D002135:Calcium-Binding Proteins; D020672:I-kappa B Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011506:Proteins; D000072099:Serrate-Jagged Proteins; D000072000:NF-KappaB Inhibitor alpha