Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH, USA.
Nat Commun. 2024 Jun 18;15(1):5180. doi: 10.1038/s41467-024-48678-3.
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.
Siglec-6 是一种凝集素受体，在胎盘、肥大细胞和记忆 B 细胞中表达受限。虽然 Siglec-6 在慢性淋巴细胞白血病（CLL）患者中表达，但它的病理生理作用尚未阐明。我们在这里描述了 Siglec-6 在体外 CLL B 细胞迁移和黏附到 CLL 骨髓基质细胞（BMSCs）以及体内向骨髓和脾脏迁移受损中的作用。质谱分析显示 Siglec-6 与鸟嘌呤核苷酸交换因子 DOCK8 相互作用。用 Siglec-6 配体 sTn 刺激 MEC1-002 CLL 细胞，导致 Cdc42 激活、WASP 蛋白募集和 F-肌动蛋白聚合，所有这些都与细胞迁移有关。在免疫功能正常的小鼠模型中，一种 Siglec-6/CD3 双特异性 T 细胞募集抗体（T-biAb）治疗可改善总生存期，并在患者来源的异种移植模型中消除 CLL 细胞。因此，我们的研究结果揭示了 Siglec-6 在 CLL 中的迁移作用，可使用针对 Siglec-6 的 T-biAb 进行治疗性靶向。
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