Differential Hox expression in murine embryonic stem cell models of normal and malignant hematopoiesis

Wheadon, H. , Ramsey, J.M., Dobbin, E., Dickson, G.J., Corrigan, P.M., Freeburn, R.W. and Thompson, A. (2011) Differential Hox expression in murine embryonic stem cell models of normal and malignant hematopoiesis. Stem Cells and Development, 20(8), pp. 1465-1476. (doi:10.1089/scd.2010.0226)

[img] Text
66381.pdf

550kB

Publisher's URL: http://online.liebertpub.com/doi/abs/10.1089/scd.2010.0226

Abstract

The Hox family are master transcriptional regulators of developmental processes, including hematopoiesis. The Hox regulators, caudal homeobox factors (Cdx1-4), and Meis1, along with several individual Hox proteins, are implicated in stem cell expansion during embryonic development, with gene dosage playing a significant role in the overall function of the integrated Hox network. To investigate the role of this network in normal and aberrant, early hematopoiesis, we employed an in vitro embryonic stem cell differentiation system, which recapitulates mouse developmental hematopoiesis. Expression profiles of Hox, Pbx1, and Meis1 genes were quantified at distinct stages during the hematopoietic differentiation process and compared with the effects of expressing the leukemic oncogene Tel/PDGFR;2. During normal differentiation the Hoxa cluster, Pbx1 and Meis1 predominated, with a marked reduction in the majority of Hox genes (27/39) and Meis1 occurring during hematopoietic commitment. Only the posterior Hoxa cluster genes (a9, a10, a11, and a13) maintained or increased expression at the hematopoietic colony stage. Cdx4, Meis1, and a subset of Hox genes, including a7 and a9, were differentially expressed after short-term oncogenic (Tel/PDGFR;2) induction. Whereas Hoxa4-10, b1, b2, b4, and b9 were upregulated during oncogenic driven myelomonocytic differentiation. Heterodimers between Hoxa7/Hoxa9, Meis1, and Pbx have previously been implicated in regulating target genes involved in hematopoietic stem cell (HSC) expansion and leukemic progression. These results provide direct evidence that transcriptional flux through the Hox network occurs at very early stages during hematopoietic differentiation and validates embryonic stem cell models for gaining insights into the genetic regulation of normal and malignant hematopoiesis.

Item Type:Articles
Additional Information:This is a copy of an article published in the journal Stem Cells and Development. © 2011 Mary Ann Liebert, Inc.; Stem Cells and Development is available online at: http://online.liebertpub.com.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Dobbin, Dr Edwina and Wheadon, Dr Helen
Authors: Wheadon, H., Ramsey, J.M., Dobbin, E., Dickson, G.J., Corrigan, P.M., Freeburn, R.W., and Thompson, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Stem Cells and Development
Publisher:Mary Ann Liebert, Inc.
ISSN:1547-3287
ISSN (Online):1557-8534
Published Online:05 January 2011
Copyright Holders:Copyright
First Published:First published in Historical Journal 2011 20(8):1465-1476
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

University Staff: Request a correction | Enlighten Editors: Update this record