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The Vitamin D₃/Hox-A10 Pathway Supports MafB Function during the Monocyte Differentiation of Human CD34⁺ Hemopoietic Progenitors¹

Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy

Although a considerable number of reports indicate an involvement of the Hox-A10 gene in the molecular control of hemopoiesis, the conclusions of such studies are quite controversial given that they support, in some cases, a role in the stimulation of stem cell self-renewal and myeloid progenitor expansion, whereas in others they implicate this transcription factor in the induction of monocyte-macrophage differentiation. To clarify this issue, we analyzed the biological effects and the transcriptome changes determined in human primary CD34⁺ hemopoietic progenitors by retroviral transduction of a full-length Hox-A10 cDNA. The results obtained clearly indicated that this homeogene is an inducer of monocyte differentiation, at least partly acting through the up-regulation of the MafB gene, recently identified as the master regulator of such a maturation pathway. By using a combined approach based on computational analysis, EMSA experiments, and luciferase assays, we were able to demonstrate the presence of a Hox-A10-binding site in the promoter region of the MafB gene, which suggested the likely molecular mechanism underlying the observed effect. Stimulation of the same cells with the vitamin D₃ monocyte differentiation inducer resulted in a clear increase of Hox-A10 and MafB transcripts, indicating the existence of a precise transactivation cascade involving vitamin D₃ receptor, Hox-A10, and MafB transcription factors. Altogether, these data allow one to conclude that the vitamin D₃/Hox-A10 pathway supports MafB function during the induction of monocyte differentiation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from Associazione Italiana per la Ricerca sul Cancro (2006) and from Ministero dell’Università e della Ricerca Scientifica e Technologica-Cofin (2007). C.G. is a fellow of the Ergentech Laboratory of Genetics and Biotechnology.

² These authors share the senior authorship of this investigation.

³ Address correspondence and requests for reprints to Dr. Alexis Grande, Dipartimento di Scienze Biomediche, Sezione di Chimica Biologica, Università di Modena e Reggio Emilia, Via Campi 287, 41100 Modena, Italy. E-mail address: grande{at}unimo.it

⁴ Abbreviations used in this paper: HSC, hemopoietic stem cells; VD, 1,25-dihydroxyvitamin D₃; HRE, Hox response element; NGFR, nerve growth factor receptor; LNGFR, low-affinity NGFR; QRT-PCR, quantitative real-time RT-PCR; SLR, signal log ratio; CTS, cathepsin; NE, nuclear extract.