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Specifically, CXCR4 signaling critically influences the dissemination of various malignant B cells through constitutive activation and aberrant expression. This study explores the interaction between CD19 and CXCR4 signaling in the context of B-cell lymphomas, particularly focusing on diffuse large B-cell lymphoma (DLBCL) and Waldenstr\u00f6m Macroglobulinemia (WM). We assessed the roles of CD19 in survival and CXCL12-induced migration by using knockout (KO) cells of DLBCL and WM origin alongside evaluating the impact of CD19 monoclonal antibodies (mAbs) on antibody-dependent cell-mediated cytotoxicity (ADCC). Our results highlight that CD19 is important for survival and CXCL12-induced migration, and mAbs variably increase CXCL12-induced migration and enhance ADCC. Additionally, we demonstrate that the endogenous peptide inhibitor of the CXCR4 (EPI-X4) derivative JM#21 effectively inhibits CD19-mediated migration enhancement and promotes ADCC, thereby augmenting the therapeutic efficacy of CD19 mAb-based immunotherapy in lymphoma models. Our study underscores the potential of targeting both CD19 and CXCR4 to refine therapeutic strategies for treating B-cell malignancies, suggesting a synergistic approach could improve clinical outcomes in WM treatment.<\/jats:p>","DOI":"10.3390\/ijms26052024","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T06:15:33Z","timestamp":1740550533000},"page":"2024","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["CXCR4 Inhibition Enhances the Efficacy of CD19 Monoclonal Antibody-Mediated Extermination of B-Cell Lymphoma"],"prefix":"10.3390","volume":"26","author":[{"given":"Nupur","family":"Khunti","sequence":"first","affiliation":[{"name":"Institute of Experimental Cancer Research, Ulm University Medical Center, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manish","family":"Kumar","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cancer Research, Ulm University Medical Center, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-6524-4804","authenticated-orcid":false,"given":"Moumita","family":"Datta","sequence":"additional","affiliation":[{"name":"Institute of Immunology, Ulm University Medical Center, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean de Dieu","family":"Harelimana","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Hygiene, Ulm University Medical Center, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5460-5166","authenticated-orcid":false,"given":"Mirja","family":"Harms","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Albers","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7052-2360","authenticated-orcid":false,"given":"Frank","family":"Kirchhoff","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7316-7141","authenticated-orcid":false,"given":"Jan","family":"M\u00fcnch","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Stenger","sequence":"additional","affiliation":[{"name":"Institute of Microbiology and Hygiene, Ulm University Medical Center, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Buske","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cancer Research, Ulm University Medical Center, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3295-5859","authenticated-orcid":false,"given":"Palash Chandra","family":"Maity","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cancer Research, Ulm University Medical Center, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1172\/JCI39748","article-title":"CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency","volume":"120","author":"Smet","year":"2010","journal-title":"J. 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