{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T04:55:59Z","timestamp":1792299359442,"version":"4.4.0"},"reference-count":60,"publisher":"American Society of Hematology","issue":"9","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,5,13]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>CXCL12-CXCR4 signaling is involved in a wide variety of homeostatic and pathologic processes, but the role of specific CXCL12 isoforms has remained largely unexplored. We have recently shown that the CXCL12\u03b3 isoform, which holds an exceptionally high affinity for heparan sulfate (HS), is produced by human bone marrow stromal cells (BMSCs) and remains cell surface immobilized by HS proteoglycans (HSPGs). This HS-bound CXCL12\u03b3 is critical for the adhesion of multiple myeloma cells to BMSCs and for BMSC-mediated drug resistance. In this study, we investigated how CXCL12\u03b3 activates and regulates CXCR4 by employing a variety of biosensors in HEK293T cells, endogenous CXCR4-expressing B-lymphoma and myeloma cell lines and primary B cells. We showed that CXCL12\u03b3 and CXCL12\u03b1 bind CXCR4 with a similar affinity and that the cumulative activation of CXCR4 over time is equal for both ligands, although CXCL12\u03b1 activates CXCR4 more rapidly. Although nonbound CXCL12\u03b3 and CXCL12\u03b1 equally induce CXCR4 internalization, cell- or heparin-bound CXCL12\u03b3 hardly induces CXCR4 internalization or desensitization. CXCL12\u03b3 presented by HSPGs on the membrane of human bone marrow endothelial cells (HBMECs) induces potent cell adhesion to the endothelium under physiological flow, but cells retain the ability to migrate toward CXCL12\u03b1 when they encounter HBMEC-bound CXCL12\u03b3. Taken together, our data demonstrate that CXCL12\u03b3 and CXCL12\u03b1 differentially modulate CXCR4 trafficking and that CXCL12\u03b3, when immobilized and presented by HSPGs on the cell surface of HBMECs, can efficiently arrest circulating cells without causing CXCR4 internalization or desensitization, thus enabling subsequent cell migration toward a CXCL12\u03b1 gradient.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/bloodadvances.2024014396","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T14:08:27Z","timestamp":1739974107000},"page":"2307-2320","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":2,"title":["Presentation of CXCL12\u03b3 by heparan sulfate proteoglycans activates CXCR4 without desensitization in normal and malignant B cells"],"prefix":"10.1182","volume":"9","author":[{"given":"Hildo C.","family":"Lantermans","sequence":"first","affiliation":[{"name":"1Department of Pathology, Amsterdam University Medical Center Location University of Amsterdam, Amsterdam, The Netherlands"},{"name":"2Lymphoma and Myeloma Center Amsterdam, Amsterdam, The Netherlands"},{"name":"3Cancer Center Amsterdam, Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fangxue","family":"Ma","sequence":"additional","affiliation":[{"name":"1Department of Pathology, Amsterdam University Medical Center Location University of Amsterdam, Amsterdam, The Netherlands"},{"name":"2Lymphoma and Myeloma Center Amsterdam, Amsterdam, The Netherlands"},{"name":"3Cancer Center Amsterdam, Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemieke","family":"Kuil","sequence":"additional","affiliation":[{"name":"1Department of Pathology, Amsterdam University Medical Center Location University of Amsterdam, Amsterdam, The Netherlands"},{"name":"2Lymphoma and Myeloma Center Amsterdam, Amsterdam, The Netherlands"},{"name":"3Cancer Center Amsterdam, Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin F. M.","family":"de Rooij","sequence":"additional","affiliation":[{"name":"1Department of Pathology, Amsterdam University Medical Center Location University of Amsterdam, Amsterdam, The Netherlands"},{"name":"2Lymphoma and Myeloma Center Amsterdam, Amsterdam, The Netherlands"},{"name":"3Cancer Center Amsterdam, Cancer Biology and Immunology, Target & Therapy Discovery, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5692-5975","authenticated-orcid":false,"given":"Nick D.","family":"Bergkamp","sequence":"additional","affiliation":[{"name":"4Amsterdam Institute for Molecular and Life Sciences, Division of Medicinal Chemistry, Department of Chemistry and Pharmaceutical Sciences, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0380-1722","authenticated-orcid":false,"given":"Werner","family":"van der Meer","sequence":"additional","affiliation":[{"name":"5Department of Medical Biochemistry, Vascular Cell Biology Laboratory, Amsterdam University Medical Center Location University of Amsterdam, Amsterdam, The Netherlands"},{"name":"6Section Molecular Cytology at Swammerdam Institute for Life Sciences, Leeuwenhoek Centre for Advanced Microscopy, University of Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaap D.","family":"van Buul","sequence":"additional","affiliation":[{"name":"5Department of Medical Biochemistry, Vascular Cell Biology Laboratory, Amsterdam University Medical Center Location University of Amsterdam, Amsterdam, The Netherlands"},{"name":"6Section Molecular Cytology at Swammerdam Institute for Life Sciences, Leeuwenhoek Centre for Advanced Microscopy, University of Amsterdam, Amsterdam, The 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