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Blood, 21 May 2009, Vol. 113, No. 21, pp. 5111-5120. Prepublished online as a Blood First Edition Paper on March 6, 2009; DOI 10.1182/blood-2008-09-180224. This Article Full Text Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2008-09-180224v1 113/21/5111    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Milsom, M. D. Articles by Williams, D. A. Search for Related Content PubMed PubMed Citation Articles by Milsom, M. D. Articles by Williams, D. A. Related Collections Hematopoiesis and Stem Cells Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS AND STEM CELLS Ectopic HOXB4 overcomes the inhibitory effect of tumor necrosis factor- on Fanconi anemia hematopoietic stem and progenitor cells Michael D. Milsom1, Bernhard Schiedlmeier2, Jeff Bailey3, Mi-Ok Kim4, Dandan Li4, Michael Jansen3, Abdullah Mahmood Ali3, Michelle Kirby3, Christopher Baum2, Leslie J. Fairbairn5, and David A. Williams1 1 Division of Hematology/Oncology Children's Hospital Boston and Harvard Stem Cell Institute, MA; 2 Department of Experimental Hematology, Hannover Medical School, Hannover, Germany; 3 Division of Experimental Hematology and 4 Center for Epidemiology and Biostatistics, Cincinnati Children's Hospital Medical Center, OH; and 5 Gene Therapy Group, Cancer Research United Kingdom Paterson Institute for Cancer Research, Manchester, United Kingdom Ectopic delivery of HOXB4 elicits the expansion of engrafting hematopoietic stem cells (HSCs). We hypothesized that inhibition of tumor necrosis factor- (TNF-) signaling may be central to the self-renewal signature of HOXB4. Because HSCs derived from Fanconi anemia (FA) knockout mice are hypersensitive to TNF-, we studied Fancc–/– HSCs to determine the physiologic effects of HOXB4 on TNF- sensitivity and the relationship of these effects to the engraftment defect of FA HSCs. Overexpression of HOXB4 reversed the in vitro hypersensitivity to TNF- of Fancc–/– HSCs and progenitors (P) and partially rescued the engraftment defect of these cells. Coexpression of HOXB4 and the correcting FA-C protein resulted in full correction compared with wild-type (WT) HSCs. Ectopic expression of HOXB4 resulted in a reduction in both apoptosis and reactive oxygen species in Fancc–/– but not WT HSC/P. HOXB4 overexpression was also associated with a significant reduction in surface expression of TNF- receptors on Fancc–/– HSC/P. Finally, enhanced engraftment was seen even when HOXB4 was expressed in a time-limited fashion during in vivo reconstitution. Thus, the HOXB4 engraftment signature may be related to its effects on TNF- signaling, and this pathway may be a molecular target for timed pharmacologic manipulation of HSC during reconstitution. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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