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Stroma-mediated dysregulation of myelopoiesis in mice lacking I kappa B alpha
Rudolf A Rupec1, Franziska Jundt, Bernd Rebholz
1Department of Dermatology, University of Munich, Frauenlobstrasse 9-11, D-80337 Munich, Germany. rudolf.rupec@med.uni-muenchen.de
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.
Insights
Inactive I kappa B alpha in liver cells triggers a Jagged1-dependent hematopoietic disorder in mice. This non-hematopoietic cell defect leads to permanent Notch1 activation and premalignant changes in neutrophils.
Area of Science:
- Developmental biology
- Hematology
- Immunology
Background:
- Hematopoiesis, the process of blood cell formation, occurs in the liver and bone marrow during development.
- Dysregulation of I kappa B alpha can lead to severe hematological disorders.
Purpose of the Study:
- To investigate the role of I kappa B alpha deficiency in hepatocytes on hematopoietic development.
- To elucidate the mechanism by which deregulated Jagged1 expression in non-hematopoietic cells impacts hematopoiesis.
Main Methods:
- Analysis of mice with ubiquitous and conditional I kappa B alpha deletion.
- Coculture experiments with I kappa B alpha-deficient hepatocytes and wild-type bone marrow cells.
- Assessment of Jagged1 and Notch1 signaling pathways.
Main Results:
- Ubiquitous I kappa B alpha deletion in mice resulted in a myeloproliferative disorder with increased colony-forming units (CFU-GEMM) and hypergranulopoiesis.
- This disorder was mediated by deregulated Jagged1 expression in I kappa B alpha-deficient hepatocytes, leading to permanent Notch1 activation in neutrophils.
- Conditional deletion of I kappa B alpha in the myeloid lineage did not induce the disease, indicating a non-cell-autonomous effect.
Conclusions:
- Non-hematopoietic cells, specifically hepatocytes with inactive I kappa B alpha, can initiate a premalignant hematopoietic disorder.
- Jagged1-mediated Notch1 activation is a key pathway in this process.
- Cell-fate decisions influencing hematopoietic disorders can be initiated by non-hematopoietic cells.
