P-selectin glycoprotein ligand regulates the interaction of multiple myeloma cells with the bone marrow microenvironment

Blood. 2012 Feb 9;119(6):1468-78. doi: 10.1182/blood-2011-07-368050. Epub 2011 Nov 16.


Interactions between multiple myeloma (MM) cells and the BM microenvironment play a critical role in the pathogenesis of MM and in the development of drug resistance by MM cells. Selectins are involved in extravasation and homing of leukocytes to target organs. In the present study, we focused on adhesion dynamics that involve P-selectin glycoprotein ligand-1 (PSGL-1) on MM cells and its interaction with selectins in the BM microenvironment. We show that PSGL-1 is highly expressed on MM cells and regulates the adhesion and homing of MM cells to cells in the BM microenvironment in vitro and in vivo. This interaction involves both endothelial cells and BM stromal cells. Using loss-of-function studies and the small-molecule pan-selectin inhibitor GMI-1070, we show that PSGL-1 regulates the activation of integrins and downstream signaling. We also document that this interaction regulates MM-cell proliferation in coculture with BM microenvironmental cells and the development of drug resistance. Furthermore, inhibiting this interaction with GMI-1070 enhances the sensitization of MM cells to bortezomib in vitro and in vivo. These data highlight the critical contribution of PSGL-1 to the regulation of growth, dissemination, and drug resistance in MM in the context of the BM microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow / metabolism*
  • Bone Marrow / pathology
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Flow Cytometry
  • Glycolipids / pharmacology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, SCID
  • Microscopy, Confocal
  • Multiple Myeloma / genetics
  • Multiple Myeloma / metabolism*
  • Multiple Myeloma / pathology
  • P-Selectin / genetics
  • P-Selectin / metabolism*
  • Protein Binding / drug effects
  • RNA Interference
  • Stromal Cells / metabolism
  • Stromal Cells / pathology
  • Tumor Microenvironment / drug effects


  • Glycolipids
  • Membrane Glycoproteins
  • P-Selectin
  • P-selectin ligand protein
  • rivipansel