Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma.
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 P13K 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.
Alsayed
Yazan
Y
University of Pittsburgh Cancer Institute, Division of Hematology/Oncology, Department of Internal Medicine, University of Pittsburgh, PA, USA.
Ngo
Hai
H
Runnels
Judith
J
Leleu
Xavier
X
Singha
Ujjal K
UK
Pitsillides
Costas M
CM
Spencer
Joel A
JA
Kimlinger
Teresa
T
Ghobrial
Joanna M
JM
Jia
Xiaoying
X
Lu
Ganwei
G
Timm
Michael
M
Kumar
Ashok
A
Côté
Daniel
D
Veilleux
Israel
I
Hedin
Karen E
KE
Roodman
G David
GD
Witzig
Thomas E
TE
Kung
Andrew L
AL
Hideshima
Teru
T
Anderson
Kenneth C
KC
Lin
Charles P
CP
Ghobrial
Irene M
IM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001596:Benzylamines; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000097:blood / Q000502:physiology*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D000080027:Cyclams; D003599:Cytoskeleton / Q000502:physiology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000097:blood / Q000235:genetics / Q000502:physiology*
D000911:Antibodies, Monoclonal; D001596:Benzylamines; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor