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Siglec-6 as a therapeutic target for cell migration and adhesion in chronic lymphocytic leukemia

Author

Listed:
  • Jessica Nunes

    (The Ohio State University
    The Ohio State University)

  • Rakeb Tafesse

    (The Ohio State University
    The Ohio State University)

  • Charlene Mao

    (The Ohio State University)

  • Matthew Purcell

    (The Ohio State University)

  • Xiaokui Mo

    (The Ohio State University)

  • Liwen Zhang

    (The Ohio State University)

  • Meixiao Long

    (The Ohio State University
    The Ohio State University)

  • Matthew G. Cyr

    (University of Florida)

  • Christoph Rader

    (University of Florida)

  • Natarajan Muthusamy

    (The Ohio State University
    The Ohio State University)

Abstract

Siglec-6 is a lectin receptor with restricted expression in the placenta, mast cells and memory B-cells. Although Siglec-6 is expressed in patients with chronic lymphocytic leukemia (CLL), its pathophysiological role has not been elucidated. We describe here a role for Siglec-6 in migration and adhesion of CLL B cells to CLL- bone marrow stromal cells (BMSCs) in vitro and compromised migration to bone marrow and spleen in vivo. Mass spectrometry analysis revealed interaction of Siglec-6 with DOCK8, a guanine nucleotide exchange factor. Stimulation of MEC1-002 CLL cells with a Siglec-6 ligand, sTn, results in Cdc42 activation, WASP protein recruitment and F-actin polymerization, which are all associated with cell migration. Therapeutically, a Siglec-6/CD3-bispecific T-cell-recruiting antibody (T-biAb) improves overall survival in an immunocompetent mouse model and eliminates CLL cells in a patient derived xenograft model. Our findings thus reveal a migratory role for Siglec-6 in CLL, which can be therapeutically targeted using a Siglec-6 specific T-biAb.

Suggested Citation

  • Jessica Nunes & Rakeb Tafesse & Charlene Mao & Matthew Purcell & Xiaokui Mo & Liwen Zhang & Meixiao Long & Matthew G. Cyr & Christoph Rader & Natarajan Muthusamy, 2024. "Siglec-6 as a therapeutic target for cell migration and adhesion in chronic lymphocytic leukemia," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48678-3
    DOI: 10.1038/s41467-024-48678-3
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