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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-\u00a0bone 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.<\/jats:p>","DOI":"10.1038\/s41467-024-48678-3","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T10:02:32Z","timestamp":1718704952000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Siglec-6 as a therapeutic target for cell migration and adhesion in chronic lymphocytic leukemia"],"prefix":"10.1038","volume":"15","author":[{"given":"Jessica","family":"Nunes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakeb","family":"Tafesse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlene","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7425-8213","authenticated-orcid":false,"given":"Matthew","family":"Purcell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9797-2687","authenticated-orcid":false,"given":"Xiaokui","family":"Mo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1696-9652","authenticated-orcid":false,"given":"Liwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meixiao","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew G.","family":"Cyr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Rader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0351-4504","authenticated-orcid":false,"given":"Natarajan","family":"Muthusamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,18]]},"reference":[{"key":"48678_CR1","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1038\/nri2056","volume":"7","author":"PR Crocker","year":"2007","unstructured":"Crocker, P. 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Assignee: U.S. Department of Health and Human Services (Washington, DC, USA). (ii) PCT\/US2022\/079656 for Siglec-6 Antibodies, Derivative Compounds and Related Uses. Assignee: University of Florida Research Foundation, Inc. (Gainesville, FL, USA). The other authors do not declare any competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5180"}}