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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 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 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 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 Hematopoiesis and Stem Cells Stem Cells in Hematology Chemokines, Cytokines, and Interleukins Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS WHIM syndrome myelokathexis reproduced in the NOD/SCID mouse xenotransplant model engrafted with healthy human stem cells transduced with C-terminus–truncated CXCR4 Toshinao Kawai1,3,4, Uimook Choi1, Lanise Cardwell1, Suk See DeRavin1, Nora Naumann1, Narda L. Whiting-Theobald1, Gilda F. Linton1, Jaehyun Moon1, Philip M. Murphy2, and Harry L. Malech1, 1 Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD; 2 Laboratory of Molecular Immunology, NIAID, NIH, Bethesda, MD; 3 Department of Gene Therapy, Institute of DNA Medicine, Jikei University School of Medicine, Tokyo, Japan; 4 Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan WHIM(warts, hypogammaglobulinemia, recurrent bacterial infection, and myelokathexis) syndrome is a rare immunodeficiency caused in many cases by autosomal dominant C-terminal truncation mutations in the 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 nonobese diabetic/severe combined immunodeficiency (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 a 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 bone marrow (BM) apoptosis or the release of transduced leukocytes into PB. However, mutated CXCR4 transgene expression further enhanced BM engraftment, but was associated with a 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: 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] 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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