Disruption of constitutive CXCR4 oligomers impairs oncogenic properties in lymphoid neoplasms
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (22)
Simon Mobach
Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam
Nick D. Bergkamp
Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam
Ziliang Ma
Department of Biomolecular Mass Spectrometry and Proteomics, Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University
Marco V. Haselager
Amsterdam University Medical Center location University of Amsterdam, Department of Hematology
Stephanie M. Anbuhl
Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam
Daphne Jurriens
Cell Biology, Neurobiology and Biophysics, Department of Biology, Faculty of Science, Utrecht University
Jelle van den Bor
Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam
Ziming Wang
Caitrin Crudden
Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam
Jamie L. Roos
Amsterdam University Medical Center location University of Amsterdam, Department of Hematology
Claudia V. Perez Almeria
Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam
Rick A. Boergonje
Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam
Martin J. Lohse
Reggie Bosma
Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam
Eric Eldering
Lymphoma and Myeloma Center Amsterdam
Marco Siderius
Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam
Wei Wu
Marcel Spaargaren
Lymphoma and Myeloma Center Amsterdam
Sanne H. Tonino
Amsterdam University Medical Center location University of Amsterdam, Department of Hematology
Arnon P. Kater
Amsterdam University Medical Center location University of Amsterdam, Department of Hematology
Martine J. Smit
Raimond Heukers
Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam