G. David Roodman

School of Medicine, Medicine, Hematology/Oncology

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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; et al. (Profiled Author: G. David Roodman)

Blood. 2007;109(7):2708-2717.

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 MMhoming and that it provides the framework for inhibitors of this pathway to be used in future clinical trials to abrogate MM trafficking. © 2007 by The American Society of Hematology.

PMID: 17119115     PMCID: PMC1852222

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