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

Abdel Kareem Azab1, Phong Quang, Feda Azab

  • 1Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.

Blood
|November 19, 2011
PubMed

Insights

P-selectin glycoprotein ligand-1 (PSGL-1) on multiple myeloma (MM) cells drives disease progression and drug resistance by interacting with the bone marrow microenvironment. Inhibiting this interaction with GMI-1070 sensitizes MM cells to chemotherapy.

Area of Science:

  • Hematology
  • Cancer Biology
  • Cellular Adhesion

Background:

  • Multiple myeloma (MM) cell interactions with the bone marrow (BM) microenvironment are crucial for MM pathogenesis and drug resistance.
  • Selectins mediate leukocyte extravasation and homing, processes relevant to MM cell dissemination and localization.

Purpose of the Study:

  • To investigate the role of P-selectin glycoprotein ligand-1 (PSGL-1) on MM cells in mediating interactions with the BM microenvironment.
  • To determine if targeting the PSGL-1/selectin interaction can overcome drug resistance in MM.

Main Methods:

  • Analysis of PSGL-1 expression on MM cells.
  • In vitro and in vivo studies assessing MM cell adhesion and homing to BM microenvironmental cells.
  • Loss-of-function studies and treatment with the pan-selectin inhibitor GMI-1070.
  • Assessment of integrin activation, downstream signaling, MM cell proliferation, and drug resistance.

Main Results:

  • PSGL-1 is highly expressed on MM cells and regulates their adhesion and homing to BM endothelial and stromal cells.
  • The PSGL-1/selectin interaction modulates integrin activation, downstream signaling, MM cell proliferation, and drug resistance.
  • Inhibition of PSGL-1/selectin interaction with GMI-1070 enhances MM cell sensitivity to bortezomib both in vitro and in vivo.

Conclusions:

  • PSGL-1 plays a critical role in MM growth, dissemination, and drug resistance within the BM microenvironment.
  • Targeting the PSGL-1/selectin axis represents a potential therapeutic strategy to improve MM treatment outcomes, particularly in overcoming drug resistance.

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