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Blood, 15 December 2004, Vol. 104, No. 13, pp. 3886-3893. Prepublished online as a Blood First Edition Paper on August 19, 2004; DOI 10.1182/blood-2004-02-0656. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-02-0656v1 104/13/3886    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 Gimeno, R. Articles by Spits, H. Search for Related Content PubMed PubMed Citation Articles by Gimeno, R. Articles by Spits, H. Related Collections Apoptosis Oncogenes and Tumor Suppressors Gene Expression Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Monitoring the effect of gene silencing by RNA interference in human CD34+ cells injected into newborn RAG2-/- c-/- mice: functional inactivation of p53 in developing T cells Ramon Gimeno, Kees Weijer, Arie Voordouw, Christel H. Uittenbogaart, Nicolas Legrand, Nuno L. Alves, Erwin Wijnands, Bianca Blom, and Hergen Spits From the Department of Cell Biology and Histology and the Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; the Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, Netherlands; and the Departments of Pediatrics, Microbiology, Immunology, and Molecular Genetics, David E. Geffen School of Medicine, University of California at Los Angeles. Tumor suppressor p53 plays an important role in regulating cell cycle progression and apoptosis. Here we applied RNA interference to study the role of p53 in human hematopoietic development in vivo. An siRNA construct specifically targeting the human tumor-suppressor gene p53 was introduced into human CD34+ progenitor cells by lentivirus-mediated gene transfer, which resulted in more than 95% knockdown of p53. We adapted the human-SCID mouse model to optimize the development of hematopoietic cells, particularly of T cells. This was achieved by the intraperitoneal injection of CD34+ precursor cells into newborn Rag2-/- c-/- mice that lack T, B, and NK cells. Robust development of T cells was observed in these mice, with peripheral T-cell repopulation 8 weeks after injection of the precursor cells. Other lymphocyte and myeloid subsets also developed in these mice. Injecting p53 siRNA-transduced CD34+ cells resulted in stable expression and down-modulation of p53 in the mature T-cell offspring. Inactivating p53 did not affect the development of CD34+ cells into various mature leukocyte subsets, including T cells, but it conferred resistance to -irradiation and other p53-dependent apoptotic stimuli to the T cells. (Blood. 2004;104:3886-3893) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. S. An, B. Poon, R. H. T. Fang, K. Weijer, B. Blom, H. Spits, I. S. Y. Chen, and C. H. Uittenbogaart Use of a Novel Chimeric Mouse Model with a Functionally Active Human Immune System To Study Human Immunodeficiency Virus Type 1 Infection Clin. Vaccine Immunol., April 1, 2007; 14(4): 391 - 396. [Abstract] [Full Text] [PDF] L. Zhang, G. I. Kovalev, and L. Su HIV-1 infection and pathogenesis in a novel humanized mouse model Blood, April 1, 2007; 109(7): 2978 - 2981. [Abstract] [Full Text] [PDF] S. Gorantla, H. Sneller, L. Walters, J. G. Sharp, S. J. Pirruccello, J. T. West, C. Wood, S. Dewhurst, H. E. Gendelman, and L. Poluektova Human Immunodeficiency Virus Type 1 Pathobiology Studied in Humanized BALB/c-Rag2-/-{gamma}c-/- Mice J. Virol., March 15, 2007; 81(6): 2700 - 2712. [Abstract] [Full Text] [PDF] M. A. Friese, X. Montalban, N. Willcox, J. I. Bell, R. Martin, and L. Fugger The value of animal models for drug development in multiple sclerosis Brain, August 1, 2006; 129(8): 1940 - 1952. [Abstract] [Full Text] [PDF] N. Legrand, T. Cupedo, A. U. van Lent, M. J. Ebeli, K. Weijer, T. Hanke, and H. Spits Transient accumulation of human mature thymocytes and regulatory T cells with CD28 superagonist in "human immune system" Rag2-/-{gamma}c-/- mice Blood, July 1, 2006; 108(1): 238 - 245. [Abstract] [Full Text] [PDF] N. Legrand, K. Weijer, and H. Spits Experimental Models to Study Development and Function of the Human Immune System In Vivo J. Immunol., February 15, 2006; 176(4): 2053 - 2058. [Abstract] [Full Text] [PDF] C. A. Sledz and B. R. G. Williams RNA interference in biology and disease Blood, August 1, 2005; 106(3): 787 - 794. [Abstract] [Full Text] [PDF]

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