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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.
 Previous Article | Next Article 
Submitted February 20, 2004
Accepted July 25, 2004
Monitoring the effect of gene silencing by RNA-interference in human CD34+ cells injected into newborn RAG2-/- gamma common-/- 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*
Department of Cell Biology & Histology, Academic Medical Center (AMC) at the University of Amsterdam, Amsterdam, The Netherlands
Department of Cell Biology & Histology, Academic Medical Center (AMC) at the University of Amsterdam, Amsterdam, The Netherlands; Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Amsterdam, The Netherlands
Departments of Pediatrics, Microbiology, Immunology and Molecular Genetics, David E. Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Department of Experimental Immunology, Academic Medical Center (AMC) at the University of Amsterdam, Amsterdam, The Netherlands
* Corresponding author; email: hergen.spits{at}amc.uva.nl.
p53 plays an important role in regulation of cell cycle progression and apoptosis. Here we applied RNA interference to study the role of p53 in human hematopoietic development in vivo. A 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 >95% knock down of p53. We adapted the human-SCID mouse model to optimize development of hematopoietic cells, in particular of T cells. This was achieved by intraperitoneal injection of CD34+ precursor cells into newborn Rag2-/- gamma common-/- mice that lack T, B and NK cells. Robust T cell development 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. Injection of p53siRNA-transduced CD34+ cells resulted in stable expression and down-modulation of p53 in the mature T cell offspring. Inactivation of p53 did not affect development of CD34+ cells into various mature leukocyte subsets, including T cells, but conferred resistance to  -irradiation and other p53-dependent apoptotic stimuli to the T cells.
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