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Blood, 1 April 2007, Vol. 109, No. 7, pp. 2708-2717. Prepublished online as a Blood First Edition Paper on November 21, 2006; DOI 10.1182/blood-2006-07-035857. This Article Full Text (PDF) All Versions of this Article: blood-2006-07-035857v1 109/7/2708    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 Alsayed, Y. Articles by Ghobrial, I. M Search for Related Content PubMed PubMed Citation Articles by Alsayed, Y. Articles by Ghobrial, I. M Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 17, 2006 Accepted November 14, 2006 Mechanisms of regulation of CXCR4/SDF-1 (CXCL12) dependent migration and homing in Multiple Myeloma Yazan Alsayed, Hai Ngo, Judith Runnels, Xavier Leleu, Ujjal K Singha, Costas M Pitsillides, Joel A Spencer, Teresa Kimlinger, Joanna M Ghobrial, Xiaoying Jia, Ganwei Lu, Michael Timm, Ashok Kumar, Daniel Cote, Israel Veilleux, Karen E Hedin, G David Roodman, Thomas E Witzig, Andrew L Kung, Teru Hideshima, Kenneth C Anderson, Charles P Lin, and Irene M Ghobrial* University of Pittsburgh Cancer Institute, Dept of Internal Medicine, University of Pittsburgh, Pittsburgh, PA, United States Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, United States Advanced Microscopy Program,Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States Mayo Clinic College of Medicine, Rochester, MN, United States Dept of Pediatric Oncology, Dana Farber Cancer Institute and Children's Hospital and Harvard Medical School, Boston, MA, United States * Corresponding author; email: irene_ghobrial{at}dfci.harvard.edu. The mechanisms by which multiple myeloma (MM) cells migrate and home to the bone marrow are not well understood. In this study, we sought to determine the effect of the chemokine SDF-1 (CXCL12) and its receptor CXCR4 on the migration and homing of MM cells. We demonstrated that CXCR4 is differentially expressed at high levels in the peripheral blood and is downregulated in the bone marrow in response to high levels of SDF-1. SDF-1 induced motility, internalization and cytoskeletal rearrangement in MM cells evidenced by confocal microscopy. The specific CXCR4 inhibitors AMD3100 and anti-CXCR4 antibody MAB171 inhibited migration of MM cells in vitro. CXCR4 Knockdown experiments demonstrated that SDF-1-dependent migration was regulated by the PI3K and ERK/MAPkinase pathways, but not by p38MAPK. In addition, we demonstrated that AMD3100 inhibited homing of MM cells to the bone marrow niches using in vivo flow cytometry, in vivo confocal microscopy, and whole body bioluminescence imaging. This study, therefore, demonstrates that SDF-1/CXCR4 is a critical regulator of MM homing, providing the framework for inhibitors of this pathway to be used in future clinical trials to abrogate MM trafficking. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. T. Ngo, A. K. Azab, M. Farag, X. Jia, M. M. Melhem, J. Runnels, A. M. Roccaro, F. Azab, A. Sacco, X. Leleu, et al. Src Tyrosine Kinase Regulates Adhesion and Chemotaxis in Waldenstrom Macroglobulinemia Clin. Cancer Res., October 1, 2009; 15(19): 6035 - 6041. [Abstract] [Full Text] [PDF] A. Kawaguchi, Y. Orba, T. Kimura, H. Iha, M. Ogata, T. Tsuji, A. Ainai, T. Sata, T. Okamoto, W. W. Hall, et al. Inhibition of the SDF-1{alpha}-CXCR4 axis by the CXCR4 antagonist AMD3100 suppresses the migration of cultured cells from ATL patients and murine lymphoblastoid cells from HTLV-I Tax transgenic mice Blood, October 1, 2009; 114(14): 2961 - 2968. 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