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Blood, 1 January 2007, Vol. 109, No. 1, pp. 78-84. Prepublished online as a Blood First Edition Paper on August 31, 2006; DOI 10.1182/blood-2006-05-025296. This Article Full Text (PDF) All Versions of this Article: blood-2006-05-025296v1 109/1/78    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 Kawai, T. Articles by Malech, H. L Search for Related Content PubMed PubMed Citation Articles by Kawai, T. Articles by Malech, H. L Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 30, 2006 Accepted August 14, 2006 WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus truncated CXCR4 Toshinao Kawai, Uimook Choi, Lanise Cardwell, Suk See DeRavin, Nora Naumann, Narda L Whiting-Theobald, Gilda F Linton, Jaehyun Moon, Philip M Murphy, and Harry L Malech* National Institute of Allergy and Infectious Diseases, NIH * Corresponding author; email: hmalech{at}nih.gov. WHIM syndrome is a rare immunodeficiency caused in many cases by autosomal dominant C-terminal truncation mutations in chemokine receptor CXCR4. A prominent and unexplained feature of WHIM is myelokathexis (hypercellularity with apoptosis of mature myeloid cells in bone marrow and neutropenia). We transduced healthy human CD34+ peripheral blood mobilized stem cells (PBSCs) with retrovirus vector encoding wild type (wt) CXCR4 or WHIM type mutated-CXCR4 and studied these cells ex vivo in culture and after engraftment in a NOD/SCID mouse xenograft model. Neither wt-CXCR4 nor mutated-CXCR4 transgene expression itself enhanced apoptosis of neutrophils arising in transduced PBSC cultures even with stimulation by CXCR4 agonist, stromal cell- derived factor-1 (SDF-1 [CXCL12]). Excess wt-CXCR4 expression by transduced human PBSCs enhanced marrow engraftment, but did not affect BM apoptosis nor release of transduced leukocytes into peripheral blood (PB). However, mutated-CXCR4 transgene expression further enhanced BM engraftment, but was associated with significant increase in apoptosis of transduced cells in BM and reduced release of transduced leukocytes into PB. We conclude that increased apoptosis of mature myeloid cells in WHIM is secondary to a failure of marrow release and progression to normal myeloid cell senescence, and not a direct effect of activation of mutated-CXCR4. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: What is WHIM syndrome? David C. Dale Blood 2007 109: 4. [Full Text] [PDF] This article has been cited by other articles: S. W. Lane, D. T. Scadden, and D. G. Gilliland The leukemic stem cell niche: current concepts and therapeutic opportunities Blood, August 6, 2009; 114(6): 1150 - 1157. [Abstract] [Full Text] [PDF] L. D. Notarangelo and R. Badolato Leukocyte trafficking in primary immunodeficiencies J. Leukoc. Biol., March 1, 2009; 85(3): 335 - 343. [Abstract] [Full Text] [PDF] S. von Vietinghoff and K. Ley Homeostatic Regulation of Blood Neutrophil Counts J. Immunol., October 15, 2008; 181(8): 5183 - 5188. [Abstract] [Full Text] [PDF] B. Lagane, K. Y. C. Chow, K. Balabanian, A. Levoye, J. Harriague, T. Planchenault, F. Baleux, N. Gunera-Saad, F. Arenzana-Seisdedos, and F. Bachelerie CXCR4 dimerization and {beta}-arrestin-mediated signaling account for the enhanced chemotaxis to CXCL12 in WHIM syndrome Blood, July 1, 2008; 112(1): 34 - 44. [Abstract] [Full Text] [PDF]

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