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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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HEMATOPOIESIS

Down-regulation of RXR{alpha} expression is essential for neutrophil development from granulocyte/monocyte progenitors

Sabine Taschner1, Christina Koesters1,2, Barbara Platzer1, Almut Jörgl1, Wilfried Ellmeier1, Thomas Benesch3, and Herbert Strobl1

1 Institute of Immunology, Medical University Vienna, Austria; 2 Competence Center for Biomolecular Therapeutics, Vienna, Austria; 3 Section of Medical Statistics, Medical University Vienna, Austria

Neutrophil granulocytes (Gs) 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{alpha}) represents the predominant NR types I and II homo- and heterodimerization partner in myeloid cells. Here we show that human myeloid progenitors express RXR{alpha} protein at sustained high levels during macrophage colony-stimulating factor (M-CSF)–induced monopoiesis. In sharp contrast, RXR{alpha} is down-regulated during G-CSF–dependent late-stage neutrophil differentiation from myeloid progenitors. Down-regulation of RXR{alpha} is critically required for neutrophil development since ectopic RXR{alpha} inhibited granulopoiesis by impairing proliferation and differentiation. Moreover, ectopic RXR{alpha} 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{alpha} signaling in hematopoietic progenitor/stem cells using a dominant-negative RXR{alpha} promoted the generation of late-stage granulocytes in human cultures in vitro and in reconstituted mice in vivo. Therefore, our data suggest that RXR{alpha} down-regulation is a critical requirement for the generation of neutrophil granulocytes.


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