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J. Biol. Chem., Vol. 282, Issue 19, 14454-14462, May 11, 2007

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The Cxcl12, Periostin, and Ccl9 Genes Are Direct Targets for Early B-cell Factor in OP-9 Stroma Cells^*

Anna Lagergren, Robert Månsson, Jenny Zetterblad, Emma Smith, Barbro Basta^¶, David Bryder, Peter Åkerblad^¶, and Mikael Sigvardsson¹

From the Department for Hematopoetic Stem Cell Biology, Lund Stemcell Center, Lund University BMC B12, S-221 84 Lund, the ^¶Department of Molecular Pharmacology, AstraZeneca R&D Mölndal, S-431 83 Mölndal, and the Department for Biomedicine and Surgery, University of Health Sciences, Linköping University, 581 85 Linköping, Sweden

The development of blood cells from hematopoietic stem cells in the bone marrow is dependent on communication with bone marrow stroma cells, making these cells central for the appropriate regulation of hematopoiesis. To identify transcription factors that may play a role in gene regulation in stroma cells, we performed comparative gene expression analysis of fibroblastic NIH3T3 cells, unable to support hematopoiesis in vitro, and OP-9 stroma cells, highly efficient in this regard. These experiments revealed that transcription factors of the early B cell factor (EBF) family were highly expressed in OP-9 cells as compared with the NIH3T3 cells. To identify potential targets genes for EBF proteins in stroma cells, we overexpressed EBF in fibroblasts and analyzed the pattern of induced genes by microarray analysis. This revealed that EBF was able to up-regulate expression of among others the Cxcl12, Ccl9, and Periostin genes. The identification of relevant promoters revealed that they all contained functional EBF binding sites able to interact with EBF in OP-9 cells. Furthermore, ectopic expression of a dominant negative EBF protein or antisense EBF-1 RNA in OP-9 stroma cells resulted in reduced expression of these target genes. These data suggest that EBF proteins might have dual roles in hematopoiesis acting both as intrinsic regulators of B-lymphopoiesis and as regulators of genes in bone marrow stroma cells.

Received for publication, November 2, 2006 , and in revised form, February 27, 2007.

^* This work was supported by the Swedish Cancer Society (Cancerfonden), The Swedish Research Council (VR), Barn Cancer, Kocks,Österlunds, and Crafoord Foundations and the Medical Faculty at Lund University, Lund Strategic Center for Stem Cell Biology and Cell Therapy are sponsored by a center grant from Stiftelsen för Strategisk Forskning. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S2.

¹ To whom correspondence should be addressed. Tel.: 46-0-462223829; Fax: 46-0-462223600; E-mail: mikael.sigvardsson{at}stemcell.lu.se.

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