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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3988-3994. Prepublished online as a Blood First Edition Paper on August 9, 2005; DOI 10.1182/blood-2005-05-2003. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: 2005-05-2003v1 106/12/3988    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lawrence, H. J. Articles by Largman, C. Search for Related Content PubMed PubMed Citation Articles by Lawrence, H. J. Articles by Largman, C. Related Collections Hematopoiesis and Stem Cells Gene Expression Stem Cells in Hematology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  STEM CELLS IN HEMATOLOGY Loss of expression of the Hoxa-9 homeobox gene impairs the proliferation and repopulating ability of hematopoietic stem cells H. Jeffrey Lawrence, Julie Christensen, Stephen Fong, Yu-Long Hu, Irving Weissman, Guy Sauvageau, R. Keith Humphries, and Corey Largman From the Division of Hematology and Medical Oncology, Department of Medicine, University of California School of Medicine, Veterans Affairs (VA) Medical Center, San Francisco, CA; Stanford University School of Medicine, Stanford, CA; the University of Montreal, Montreal, QC, Canada; and the British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada. The homeobox gene Hoxa-9 is normally expressed in primitive bone marrow cells, and overexpression of Hoxa-9 markedly expands hematopoietic stem cells, suggesting a function in early hematopoiesis. We present evidence for major functional defects in Hoxa-9-/- hematopoietic stem cells. Hoxa-9-/- marrow cells have normal numbers of immunophenotypic stem cells (Lin-c-kit+flk-2-Sca-1+ [KLFS] cells). However, sublethally irradiated Hoxa-9-/- mice develop persistent pancytopenia, indicating unusual sensitivity to ionizing irradiation. In competitive transplantation assays, Hoxa-9-/- cells showed an 8-fold reduction in multilineage long-term repopulating ability, a defect not seen in marrow cells deficient for the adjacent Hoxa-10 gene. Single-cell cultures of KLFS cells showed a 4-fold reduction in large high-proliferation potential colonies. In liquid cultures, Hoxa-9-deficient Lin-Sca-1+ cells showed slowed proliferation (a 5-fold reduction in cell numbers at day 8) and delayed emergence of committed progenitors (a 5-fold decrease in colony-forming cells). Slowing of proliferation was accompanied by a delay in myeloid maturation, with a decrease in Gr-1hiMac-1hi cells at the end of the culture. Retroviral transduction with a Hoxa-9 expression vector dramatically enhanced the cytokine-driven proliferation and in vivo engraftment of Hoxa-9-/- marrow cells. Hoxa-9 appears to be specifically required for normal hematopoietic stem cell function both in vitro and in vivo. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: The wizard of Hox Curt I. Civin Blood 2005 106: 3682-3683. [Full Text] [PDF] This article has been cited by other articles: S. R. Horman, C. S. Velu, A. Chaubey, T. Bourdeau, J. Zhu, W. E. Paul, B. Gebelein, and H. L. 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Kamps Persistent Transactivation by Meis1 Replaces Hox Function in Myeloid Leukemogenesis Models: Evidence for Co-Occupancy of Meis1-Pbx and Hox-Pbx Complexes on Promoters of Leukemia-Associated Genes Mol. Cell. Biol., May 15, 2006; 26(10): 3902 - 3916. [Abstract] [Full Text] [PDF] G. V. Priestley, L. M. Scott, T. Ulyanova, and T. Papayannopoulou Lack of {alpha}4 integrin expression in stem cells restricts competitive function and self-renewal activity Blood, April 1, 2006; 107(7): 2959 - 2967. [Abstract] [Full Text] [PDF]

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