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Blood, 1 February 2007, Vol. 109, No. 3, pp. 971-979.
Prepublished online as a Blood First Edition Paper on October 3, 2006; DOI 10.1182/blood-2006-04-020552.
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Submitted April 28, 2006
Accepted September 12, 2006
Downregulation of RXR expression is essential for neutrophil development from granulocyte/monocyte progenitors
Sabine Taschner, Christina Koesters, Barbara Platzer, Almut Jorgl, Wilfried Ellmeier, Thomas Benesch, and Herbert Strobl*
Institute of Immunology, Medical University Vienna, Vienna, Austria
Competence Center for Biomolecular Therapeutics, Vienna, Austria
Section of Medical Statistics, Medical University Vienna, Vienna, Austria
* Corresponding author; email: herbert.strobl{at}meduniwien.ac.at.
Neutrophil granulocytes (G) represent highly abundant and short-lived leukocytes that are constantly regenerated from a small pool of myeloid committed progenitors. Nuclear receptor (NR) family members are ligand-activated transcription factors that play key roles in cellular proliferation and differentiation processes including myelopoiesis. Retinoid X receptor alpha (RXR ) represents the predominant NR type I and II homo- and heterodimerization partner in myeloid cells. Here we show that human myeloid progenitors express RXR protein at sustained high levels during M-CSF-induced monopoiesis. In sharp contrast, RXR is downregulated during G-CSF-dependent late-stage neutrophil differentiation from myeloid progenitors. Downregulation of RXR is critically required for neutrophil development since ectopic RXR inhibited granulopoiesis by impairing proliferation and differentiation. Moreover ectopic RXR was sufficient to redirect G-CSF-dependent granulocyte differentiation to the monocyte lineage and to promote M-CSF-induced monopoiesis. Functional genetic interference with RXR signaling in hematopoietic progenitor/stem cells using a dominant-negative RXR promoted the generation of late-stage granulocytes in human cultures in vitro and in reconstituted mice in vivo. Therefore, our data suggest that RXR downregulation is a critical requirement for the generation of neutrophil granulocytes.
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