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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 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 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 Alsayed, Y. Articles by Ghobrial, I. M. Search for Related Content PubMed PubMed Citation Articles by Alsayed, Y. Articles by Ghobrial, I. M. Related Collections Neoplasia Cell Adhesion and Motility Signal Transduction Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CHEMOKINES, CYTOKINES, AND INTERLEUKINS Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)–dependent migration and homing in multiple myeloma Yazan Alsayed1, Hai Ngo2, Judith Runnels3, Xavier Leleu2, Ujjal K. Singha1, Costas M. Pitsillides3, Joel A. Spencer3, Teresa Kimlinger4, Joanna M. Ghobrial4, Xiaoying Jia2, Ganwei Lu1, Michael Timm4, Ashok Kumar4, Daniel Côté3, Israel Veilleux3, Karen E. Hedin4, G. David Roodman1, Thomas E. Witzig4, Andrew L. Kung5, Teru Hideshima2, Kenneth C. Anderson2, Charles P. Lin3, and Irene M. Ghobrial2 1 University of Pittsburgh Cancer Institute, Division of Hematology/Oncology, Department of Internal Medicine, University of Pittsburgh, PA; 2 Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; 3 Advanced Microscopy Program, Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston; 4 Mayo Clinic College of Medicine, Rochester, MN; 5 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital and Harvard Medical School, Boston, MA 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 down-regulated 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 inhibitor AMD3100 and the anti-CXCR4 antibody MAB171 inhibited the migration of MM cells in vitro. CXCR4 knockdown experiments demonstrated that SDF-1–dependent migration was regulated by the PI3K and ERK/MAPK pathways but not by p38 MAPK. In addition, we demonstrated that AMD3100 inhibited the 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 and that it provides the framework for inhibitors of this pathway to be used in future clinical trials to abrogate MM trafficking. 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