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

Jessica Nunes, Rakeb Tafesse, Charlene Mao, Matthew Purcell, Xiaokui Mo, Liwen Zhang, Meixiao Long, Matthew G. Cyr, Christoph Rader and Natarajan Muthusamy ()
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Jessica Nunes: The Ohio State University
Rakeb Tafesse: 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
Matthew G. Cyr: University of Florida
Christoph Rader: University of Florida
Natarajan Muthusamy: The Ohio State University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48678-3

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