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Blood, 1 May 2007, Vol. 109, No. 9, pp. 3687-3696.
Prepublished online as a Blood First Edition Paper on January 18, 2007; DOI 10.1182/blood-2006-10-054676.
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Submitted October 27, 2006
Accepted December 30, 2006
HOXA10 is a critical regulator for hematopoietic stem
cells and erythroid/megakaryocyte development
Mattias Magnusson, Ann CM Brun, Noriko Miyake, Jonas Larsson, Mats Ehinger, Jon Mar Bjornsson, Anton Wutz, Mikael Sigvardsson, and Stefan Karlsson*
Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University Hospital, Lund, Sweden
Department of Pathology, Lund University Hospital, Lund, Sweden
Whitehead Institute for Biomedical Research, Cambridge, MA, United States
Hematopoietic Stem Cell Laboratory, Institute of Laboratory Medicine, Lund University Hospital, Lund, Sweden
* Corresponding author; email: stefan.karlsson{at}med.lu.se.
The Homeobox (Hox) transcription factors are important regulators of normal and malignant hematopoiesis since they control proliferation, differentiation and self-renewal of hematopoietic cells at different levels of the hematopoietic hierarchy. In transgenic mice we show that the expression of HOXA10 is tightly regulated by doxycycline. Intermediate concentrations of HOXA10 induced a 15-fold increase in the repopulating capacity of hematopoietic stem cells (HSC) after 13 days of in vitro culture. Notably, the proliferation induction of HSC by HOXA10 was dependent on the HOXA10 concentration, since high levels of HOXA10 had a no effect on HSC proliferation. Furthermore, high levels of HOXA10 blocked erythroid and megakaryocyte development demonstrating that tight regulation of HOXA10 is critical for normal development of the erythroid and megakaryocytic lineages. The HOXA10-mediated effects on hematopoietic cells were associated with altered expression of genes that govern stem cell self-renewal and lineage commitment e.g. Hepatic leukemia factor(HLF), Dickkopf-1(Dkk-1), Growth factor independent-1(Gfi-1) and Gata-1. Interestingly, binding sites for HOXA10 were found in HLF, Dkk-1 and Gata-1 and Dkk-1 and Gfi-1 were transcriptionally activated by HOXA10. These findings reveal novel molecular pathways that act downstream of HOXA10 and identify HOXA10 as a master regulator of postnatal hematopoietic development.
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