Defining the Biochemical Role of Sialic Acid-Binding Immunoglobulin-like Lectin-6 in Adhesion and Migration in Chronic Lymphocytic Leukemia

Introduction: Sialic acid-binding immunoglobulin-like lectins (Siglec) are a group of lectins that regulate innate and adaptive immune function via glycan recognition. We and others have shown overexpression of Siglec-6, a member of Siglec family, on B cells from patients with chronic lymphocytic leukemia (CLL) compared to normal donor derived B cells. While placental expression of Siglec-6 has been shown to regulate invasion of trophoblast cells by binding to glycodelin, the biochemical role of Siglec-6 in CLL patients is not known. We describe here for the first time the functional relevance of Siglec-6 and its ligand sialyl Tn (sTn) in cell adhesion and migration in CLL. Biochemical mechanisms of Siglec-6 mediated cell adhesion and migration through DOCK8 dependent activation of Cdc42 associated with actin polymerization in CLL cells are presented. Further, the physiological relevance of Siglec-6/ DOCK8 axis in CLL cell adhesion and migration is validated using primary CLL patient samples, and genetically engineered loss of function Siglec-6 and DOCK8 mutant MEC1 CLL cell line. These studies thus elucidate the biological role of Siglec-6 in malignant CLL B cells and demonstrate therapeutic opportunities targeting Siglec-6 in CLL.