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Disruption of constitutive CXCR4 oligomers impairs oncogenic properties in lymphoid neoplasms

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Title: Disruption of constitutive CXCR4 oligomers impairs oncogenic properties in lymphoid neoplasms
Authors: Simon Mobach, Nick D. Bergkamp, Ziliang Ma, Marco V. Haselager, Stephanie M. Anbuhl, Daphne Jurriens, Jelle van den Bor, Ziming Wang, Caitrin Crudden, Jamie L. Roos, Claudia V. Perez Almeria, Rick A. Boergonje, Martin J. Lohse, Reggie Bosma, Eric Eldering, Marco Siderius, Wei Wu, Marcel Spaargaren, Sanne H. Tonino, Arnon P. Kater, Martine J. Smit, Raimond Heukers
Source: Proceedings of the National Academy of Sciences. 122
Publisher Information: Proceedings of the National Academy of Sciences, 2025.
Publication Year: 2025
Subject Terms: CXCR4, Tumor, Leukemia, Carcinogenesis, receptor oligomerization, leukemia, CXCR4/metabolism, Cell Movement/drug effects, drug sensitization, Molecular Processes and Therapies [Topic 2], Lymphocytic, Cell Line, SDG 3 - Good Health and Well-being, Cardiovascular and Metabolic Diseases, B-Cell/metabolism, Receptors, Humans, Chronic, Protein Multimerization, Signal Transduction
Description: 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.
Document Type: Article
File Description: application/pdf
Language: English
ISSN: 1091-6490
0027-8424
DOI: 10.1073/pnas.2424186122
Access URL: https://edoc.mdc-berlin.de/id/eprint/25432/2/25432suppl.pdf
Rights: CC BY NC ND
Accession Number: edsair.doi.dedup.....b6c184d5f5df017c103bfa351d3a1743
Database: OpenAIRE
Description
Abstract: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.
ISSN:10916490
00278424
DOI:10.1073/pnas.2424186122