SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-03-0767. This Article Full Text (PDF) All Versions of this Article: 2002-03-0767v1 101/5/1759    most recent Alert me when this article is cited Alert me if a correction is posted 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 Schiedlmeier, B. Articles by Ostertag, W. Search for Related Content PubMed PubMed Citation Articles by Schiedlmeier, B. Articles by Ostertag, W. Social Bookmarking                   What's this? Submitted March 11, 2002 Accepted September 17, 2002 High level ectopic HOXB4 expression confers a profound in vivo competitive growth advantage to human cord blood CD34+ cells, but impairs lymphomyeloid differentiation Bernhard Schiedlmeier, Hannes Klump, Elke Will, Goekhan Arman-Kalcek, Zhixiong Li, Zheng Wang, Andreas Rimek, Jutta Friel, Christopher Baum, and Wolfram Ostertag* Department of Cell and Virus Genetics, Heinrich-Pette-Institute, Hamburg, Germany Department of Hematology and Oncology, Hannover Medical School, Hannover, Germany * Corresponding author; email: wolfram.ostertag{at}hpi.uni-hamburg.de. Ectopic retroviral expression of HOXB4 causes an accelerated and enhanced regeneration of murine hematopoietic stem cells (HSCs) and is not known to compromise any program of lineage differentiation. To test the proposed hypothesis that HOXB4 could become a prime tool for in vivo expansion of genetically modified human HSCs, we retrovirally overexpressed HOXB4 together with GFP as a reporter protein in purified cord blood (CB) CD34+ cells, and evaluated the impact of ectopic HOXB4 expression on proliferation and differentiation in vitro and in vivo. When injected into NOD/SCID mice alone or in competition with control vector-transduced cells, HOXB4 overexpressing cord blood CD34+ cells had a selective growth advantage in vivo, which resulted in a marked enhancement of the primitive CD34+ population (p=0.01). However, high HOXB4 expression substantially impaired the myeloerythroid differentiation program which was reflected in a severe reduction of erythroid and myeloid progenitors in vitro (p<0.03) and in vivo (p=0.01). Furthermore, HOXB4 overexpression also significantly reduced B-cell output (p< 0.01). These results show for the first time unwanted side-effects of ectopic HOXB4 expression and therefore underscore the need to carefully determine the therapeutic window of HOXB4 expression levels before initiating clinical trials. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. D. Milsom, B. Schiedlmeier, J. Bailey, M.-O. Kim, D. Li, M. Jansen, A. M. Ali, M. Kirby, C. Baum, L. J. Fairbairn, et al. Ectopic HOXB4 overcomes the inhibitory effect of tumor necrosis factor-{alpha} on Fanconi anemia hematopoietic stem and progenitor cells Blood, May 21, 2009; 113(21): 5111 - 5120. [Abstract] [Full Text] [PDF] K.-M. Chan, S. Bonde, H. Klump, and N. Zavazava Hematopoiesis and immunity of HOXB4-transduced embryonic stem cell-derived hematopoietic progenitor cells Blood, March 15, 2008; 111(6): 2953 - 2961. [Abstract] [Full Text] [PDF] A. Rizo, B. Dontje, E. Vellenga, G. de Haan, and J. J. Schuringa Long-term maintenance of human hematopoietic stem/progenitor cells by expression of BMI1 Blood, March 1, 2008; 111(5): 2621 - 2630. [Abstract] [Full Text] [PDF] U. Modlich, J. Bohne, M. Schmidt, C. von Kalle, S. Knoss, A. Schambach, and C. Baum Cell-culture assays reveal the importance of retroviral vector design for insertional genotoxicity Blood, October 15, 2006; 108(8): 2545 - 2553. [Abstract] [Full Text] [PDF] J. P. Chute, G. G. Muramoto, J. Whitesides, M. Colvin, R. Safi, N. J. Chao, and D. P. McDonnell Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells PNAS, August 1, 2006; 103(31): 11707 - 11712. [Abstract] [Full Text] [PDF] L. Wang, P. Menendez, F. Shojaei, L. Li, F. Mazurier, J. E. Dick, C. Cerdan, K. Levac, and M. Bhatia Generation of hematopoietic repopulating cells from human embryonic stem cells independent of ectopic HOXB4 expression J. Exp. Med., May 9, 2005; (2005) jem.20041888. [Abstract] [Full Text] [PDF] S. Karlsson Stem cell expansion: success and complexities Blood, October 15, 2004; 104(8): 2210 - 2211. [Full Text] [PDF] K. Kirito, N. Fox, and K. Kaushansky Thrombopoietin Induces HOXA9 Nuclear Transport in Immature Hematopoietic Cells: Potential Mechanism by Which the Hormone Favorably Affects Hematopoietic Stem Cells Mol. Cell. Biol., August 1, 2004; 24(15): 6751 - 6762. [Abstract] [Full Text] [PDF] M. Schwieger, J. Lohler, M. Fischer, U. Herwig, D. G. Tenen, and C. Stocking A dominant-negative mutant of C/EBP{alpha}, associated with acute myeloid leukemias, inhibits differentiation of myeloid and erythroid progenitors of man but not mouse Blood, April 1, 2004; 103(7): 2744 - 2752. [Abstract] [Full Text] [PDF] J. Zhu, D. M. Giannola, Y. Zhang, A. J. Rivera, and S. G. Emerson NF-Y cooperates with USF1/2 to induce the hematopoietic expression of HOXB4 Blood, October 1, 2003; 102(7): 2420 - 2427. [Abstract] [Full Text] [PDF] J. M. Bjornsson, N. Larsson, A. C. M. Brun, M. Magnusson, E. Andersson, P. Lundstrom, J. Larsson, E. Repetowska, M. Ehinger, R. K. Humphries, et al. Reduced Proliferative Capacity of Hematopoietic Stem Cells Deficient in Hoxb3 and Hoxb4 Mol. Cell. Biol., June 1, 2003; 23(11): 3872 - 3883. [Abstract] [Full Text] [PDF]

	Copyright © 2002 by American Society of Hematology         Online ISSN: 1528-0020