Siglec-6 as a therapeutic target for cell migration and adhesion in chronic lymphocytic leukemia.
Nat Commun
; 15(1): 5180, 2024 Jun 18.
Article
in En
| MEDLINE
| ID: mdl-38890323
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Leukemia, Lymphocytic, Chronic, B-Cell
/
Cell Adhesion
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Cell Movement
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Lectins
Limits:
Animals
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Female
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Humans
/
Male
Language:
En
Journal:
Nat Commun
Year:
2024
Document type:
Article