Disruption of constitutive CXCR4 oligomers impairs oncogenic properties in lymphoid neoplasms
The chemokine receptor CXCR4 is overexpressed in many cancers and contributes to pathogenesis, disease progression, and resistance to therapies. CXCR4 is known to form oligomers, but the potential functional relevance in malignancies remains elusive. Using a nanobody-based BRET method, we demonstrate that oligomerization of endogenous CXCR4 on lymphoid cancer cell lines correlates with enhanced expression levels. Specific disruption of CXCR4 oligomers reduced basal cell migration and prosurvival signaling via changes in the phosphoproteome, indicating the existence of constitutive CXCR4 oligomer-mediated signaling. Oligomer disruption also inhibited growth of primary CLL 3D spheroids and sensitized primary malignant cells to clinically used Bcl-2 inhibitor venetoclax. Given its limited efficacy in some patients and the ability to develop resistance, sensitizing malignant B cells to venetoclax is of clinical relevance. Taken together, we established a noncanonical and critical role for CXCR4 oligomers in lymphoid neoplasms and demonstrated that their selective targeting has clinical potential.
Authors
- Caitrin Crudden (ORCID: https://orcid.org/0000-0002-7786-112X)
- Marco Siderius (ORCID: https://orcid.org/0000-0003-3630-4228)
- Nick D. Bergkamp (ORCID: https://orcid.org/0000-0001-5692-5975)
- Marco V. Haselager (ORCID: https://orcid.org/0000-0002-1410-7285)
- Daphne Jurriens (ORCID: https://orcid.org/0000-0001-5123-3099)
- Sanne H. Tonino (ORCID: https://orcid.org/0000-0002-3253-8759)
- Martine J. Smit (ORCID: https://orcid.org/0000-0003-2713-0238)
- Marcel Spaargaren (ORCID: https://orcid.org/0000-0002-3135-5109)
- Claudia V. Perez Almeria (ORCID: https://orcid.org/0000-0002-7312-8529)
- Eric Eldering (ORCID: https://orcid.org/0000-0003-0561-6640)
- Wei Wu (ORCID: https://orcid.org/0000-0002-7097-2150)
- Ziliang Ma (ORCID: https://orcid.org/0000-0003-4285-6598)
- Arnon Philip Kater (ORCID: https://orcid.org/0000-0003-3190-1891)
- Reggie Bosma (ORCID: https://orcid.org/0000-0003-3591-1376)
- Raimond Heukers (ORCID: https://orcid.org/0000-0003-4498-7751)
- Jelle van den Bor (ORCID: https://orcid.org/0000-0002-2411-2379)
- Stephanie M. Anbuhl
- Martin J. Lohse (ORCID: https://orcid.org/0000-0002-0599-3510)
- Ziming Wang (ORCID: https://orcid.org/0000-0002-5457-8882)
- Simon Mobach (ORCID: https://orcid.org/0000-0001-8320-214X)
- Jamie L. Roos
- Rick A. Boergonje
Institutions
- Agency for Science, Technology and Research (SG)
- Target (United States) (US)
- National University of Singapore (SG)
- Utrecht University (NL)
- Max Delbrück Center (DE)
- Dutch Cancer Society (NL)
- Singapore Immunology Network (SG)
- Technology Holding (United States) (US)
- Bioscience Research (US)
- IONICS Mass Spectrometry (Canada) (CA)
- Lymphoma Research Foundation (US)
- Nederlandse Vereniging voor Heelkunde (NL)
- Amsterdam University Medical Centers (NL)
- Institute of Infection and Immunity (CA)
- Cancer Center Amsterdam (NL)
- Vrije Universiteit Amsterdam (NL)
- University of Amsterdam (NL)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-06-11
- DOI
- https://doi.org/10.1073/pnas.2424186122
- Citations
- 1
- Primary Topic
- Chemokine receptors and signaling
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- European Commission
- ZonMw
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Horizon 2020 Framework Programme
- HORIZON EUROPE Marie Sklodowska-Curie Actions