Mobilization of myeloma cells involves SDF-1/CXCR4 signaling and downregulation of VLA-4.
Adhesion molecules and stromal cell-derived factor-1 (SDF-1)/CXCR4 signaling play key roles in homing and mobilization of hematopoietic stem cells (HSC). Active signaling through SDF-1/CXCR4 and upregulation of adhesion molecules are required for homing, whereas downregulation of adhesion molecules and disruption of SDF-1/CXCR4 signaling are required for mobilization of HSC. We studied the surface expression of CXCR4 very late activation antigen (VLA)-4 and VLA-5 on myeloma cells mobilized with cyclophosphamide and GM-CSF in 12 multiple myeloma patients undergoing HSC mobilization for autologous transplantation. We also studied the plasma levels of SDF-1 in apheresis collection of these patients. We observed a statistically significant decrease in the levels of SDF-1 and surface expression of CXCR4 on myeloma cells in four consecutive apheresis collections compared with premobilization bone marrow specimens. We also observed a statistically significant decrease in surface expression of VLA-4 in myeloma cells in the apheresis collections compared with premobilization bone marrow samples. Furthermore, myeloma cells derived from apheresis collections had decreased adhesion and trans-stromal migration in response to SDF-1, which could be reversed by short incubation with interleukin-6. Hence, mobilization of myeloma cells involves SDF-1/CXCR4 signaling and downregulation of VLA-4.
Gazitt
Yair
Y
University of Texas Health Science Center, San Antonio, Texas 78284, USA. gazitt@uthscsa.edu
Akay
Cagla
C
D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D003520:Cyclophosphamide / Q000494:pharmacology; D015536:Down-Regulation / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000276:immunology / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000276:immunology; D015850:Interleukin-6 / Q000494:pharmacology; D009101:Multiple Myeloma / Q000276:immunology / Q000503:physiopathology*; D009362:Neoplasm Metastasis; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology; D014407:Tumor Cells, Cultured
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D015850:Interleukin-6; D019718:Receptors, CXCR4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide