SDF-1/CXCR4 and VLA-4 interaction regulates homing in Waldenstrom macroglobulinemia.
Waldenstrom macroglobulinemia (WM) is characterized by widespread involvement of the bone marrow at the time of diagnosis, implying continuous homing of WM cells into the marrow. The mechanisms by which trafficking of the malignant cells into the bone marrow has not been previously elucidated. In this study, we show that WM cells express high levels of chemokine and adhesion receptors, including CXCR4 and VLA-4. We showed that CXCR4 was essential for the migration and trans-endothelial migration of WM cells under static and dynamic shear flow conditions, with significant inhibition of migration using CXCR4 knockdown or the CXCR4 inhibitor AMD3100. Similarly, CXCR4 or VLA-4 inhibition led to significant inhibition of adhesion to fibronectin, stromal cells, and endothelial cells. Decreased adhesion of WM cells to stromal cells by AMD3100 led to increased sensitivity of these cells to cytotoxicity by bortezomib. To further investigate the mechanisms of CXCR4-dependent adhesion, we showed that CXCR4 and VLA-4 directly interact in response to SDF-1, we further investigated downstream signaling pathways regulating migration and adhesion in WM. Together, these studies demonstrate that the CXCR4/SDF-1 axis interacts with VLA-4 in regulating migration and adhesion of WM cells in the bone marrow microenvironment.
Ngo
Hai T
HT
Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Leleu
Xavier
X
Lee
Jack
J
Jia
Xiaoying
X
Melhem
Molly
M
Runnels
Judith
J
Moreau
Anne-Sophie
AS
Burwick
Nicholas
N
Azab
Abdel Kareem
AK
Roccaro
Aldo
A
Azab
Feda
F
Sacco
Antonio
A
Farag
Mena
M
Sackstein
Robert
R
Ghobrial
Irene M
IM
D001483:Base Sequence; D001596:Benzylamines; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D054377:Chemokine CXCL12 / Q000502:physiology*; D000080027:Cyclams; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D020935:MAP Kinase Signaling System; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000473:pathology / Q000502:physiology; D008258:Waldenstrom Macroglobulinemia / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*
D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D005353:Fibronectins; D006571:Heterocyclic Compounds; D039041:Integrin alpha4beta1; D019869:Phosphatidylinositol 3-Kinases; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C088327:plerixafor