Hoxa cluster genes determine the proliferative activity of adult mouse hematopoietic stem and progenitor cells

Lebert-Ghali, Charles-�tienne; Fournier, Marilaine; Kettyle, Laura M.J.; Thompson, Alexander; Sauvageau, Guy; Bijl, Janet J.

Abstract

Determination of defined roles for endogenous homeobox (Hox) genes in adult hematopoietic stem and progenitor cell (HSPC) activity has been hampered by a combination of embryonic defects and functional redundancy. Here we show that conditional homozygous deletion of the Hoxa cluster (Hoxa−/−) results in a marked reduction of adult HSPC activity, both in vitro and in vivo. Specifically, proliferation of Hoxa−/− HSPCs is reduced compared with wild-type (WT) cells in vitro and they are less competitive in vivo. Notably, the loss of Hoxa genes had little impact on HSPC differentiation. Comparative RNA sequencing analyses of Hoxa−/− and WT hematopoietic stem cells (CD150+/CD48−/Lineage−/c-kit+/Sca-1+) identified a large number of differentially expressed genes, three of which (Nr4a3, Col1a1, and Hnf4a) showed >10-fold reduced levels. Engineered overexpression of Hoxa9 in Hoxa−/− HSPCs resulted in partial phenotypic rescue in vivo with associated recovery in expression of a large proportion of deregulated genes. Together, these results provide definitive evidence linking Hoxa gene expression to proliferation of adult HSPCs.

Citation

Lebert-Ghali, C.-É., Fournier, M., Kettyle, L. M., Thompson, A., Sauvageau, G., & Bijl, J. J. (2016). Hoxa cluster genes determine the proliferative activity of adult mouse hematopoietic stem and progenitor cells. Blood, 127(1), 87-90. https://doi.org/10.1182/blood-2015-02-626390

• Journal Article Type: Article
• Acceptance Date: Oct 26, 2015
• Online Publication Date: Nov 19, 2015
• Publication Date: Jan 7, 2016
• Deposit Date: Nov 9, 2016
• Publicly Available Date: Nov 9, 2016
• Journal: Blood
• Print ISSN: 0006-4971
• Electronic ISSN: 1528-0020
• Publisher: American Society of Hematology
• Peer Reviewed: Peer Reviewed
• Volume: 127
• Issue: 1
• Pages: 87-90
• DOI: https://doi.org/10.1182/blood-2015-02-626390
• Public URL: https://nottingham-repository.worktribe.com/output/773403
• Publisher URL: http://dx.doi.org/10.1182/blood-2015-02-626390
• Additional Information: This research was originally published in Blood. Charles-Étienne Lebert-Ghali, Marilaine Fournier, Laura Kettyle, Alexander Thompson, Guy Sauvageau and Janet J. Bijl; Blood 2016 127: pp. 87-90; doi:10.1182/blood-2015-02-626390 © the American Society of Hematology.
• Contract Date: Nov 9, 2016