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 Côté, Israel Veilleux, Karen Elaine Hedin, G. David Roodman, Thomas Elmer Witzig, Andrew L. Kung, Teru Hideshima & 3 others Kenneth C. Anderson, Charles P. Lin, Irene M. Ghobrial

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2708-2717
Number of pages10
JournalBlood
Volume109
Issue number7
DOIs
StatePublished - Apr 1 2007

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Multiple Myeloma
Bone
Confocal microscopy
CXCR4 Receptors
Bioluminescence
Flow cytometry
p38 Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinases
Chemokines
Confocal Microscopy
Blood
Bone Marrow
Imaging techniques
Whole Body Imaging
MAP Kinase Signaling System
Antibodies
Bone Marrow Cells
Anti-Idiotypic Antibodies
Flow Cytometry
Experiments

ASJC Scopus subject areas

  • Hematology

Cite this

Alsayed, Y., Ngo, H., Runnels, J., Leleu, X., Singha, U. K., Pitsillides, C. M., ... Ghobrial, I. M. (2007). Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood, 109(7), 2708-2717. https://doi.org/10.1182/blood-2006-07-035857

Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. / Alsayed, Yazan; Ngo, Hai; Runnels, Judith; Leleu, Xavier; Singha, Ujjal K.; Pitsillides, Costas M.; Spencer, Joel A.; Kimlinger, Teresa; Ghobrial, Joanna M.; Jia, Xiaoying; Lu, Ganwei; Timm, Michael; Kumar, Ashok; Côté, Daniel; Veilleux, Israel; Hedin, Karen Elaine; Roodman, G. David; Witzig, Thomas Elmer; Kung, Andrew L.; Hideshima, Teru; Anderson, Kenneth C.; Lin, Charles P.; Ghobrial, Irene M.

In: Blood, Vol. 109, No. 7, 01.04.2007, p. 2708-2717.

Research output: Contribution to journalArticle

Alsayed, Y, Ngo, H, Runnels, J, Leleu, X, Singha, UK, Pitsillides, CM, Spencer, JA, Kimlinger, T, Ghobrial, JM, Jia, X, Lu, G, Timm, M, Kumar, A, Côté, D, Veilleux, I, Hedin, KE, Roodman, GD, Witzig, TE, Kung, AL, Hideshima, T, Anderson, KC, Lin, CP & Ghobrial, IM 2007, 'Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma', Blood, vol. 109, no. 7, pp. 2708-2717. https://doi.org/10.1182/blood-2006-07-035857
Alsayed Y, Ngo H, Runnels J, Leleu X, Singha UK, Pitsillides CM et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood. 2007 Apr 1;109(7):2708-2717. https://doi.org/10.1182/blood-2006-07-035857
Alsayed, Yazan ; Ngo, Hai ; Runnels, Judith ; Leleu, Xavier ; Singha, Ujjal K. ; Pitsillides, Costas M. ; Spencer, Joel A. ; Kimlinger, Teresa ; Ghobrial, Joanna M. ; Jia, Xiaoying ; Lu, Ganwei ; Timm, Michael ; Kumar, Ashok ; Côté, Daniel ; Veilleux, Israel ; Hedin, Karen Elaine ; Roodman, G. David ; Witzig, Thomas Elmer ; Kung, Andrew L. ; Hideshima, Teru ; Anderson, Kenneth C. ; Lin, Charles P. ; Ghobrial, Irene M. / Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. In: Blood. 2007 ; Vol. 109, No. 7. pp. 2708-2717.
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AU - Pitsillides, Costas M.

AU - Spencer, Joel A.

AU - Kimlinger, Teresa

AU - Ghobrial, Joanna M.

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AU - Lu, Ganwei

AU - Timm, Michael

AU - Kumar, Ashok

AU - Côté, Daniel

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AU - Roodman, G. David

AU - Witzig, Thomas Elmer

AU - Kung, Andrew L.

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AU - Lin, Charles P.

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N2 - 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.

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