Related Experiment Video

Updated: Jun 12, 2025

A Flow Cytometry-based Assay to Identify Compounds That Disrupt Binding of Fluorescently-labeled CXC Chemokine Ligand 12 to CXC Chemokine Receptor 4
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A Flow Cytometry-based Assay to Identify Compounds That Disrupt Binding of Fluorescently-labeled CXC Chemokine Ligand 12 to CXC Chemokine Receptor 4

Published on: March 10, 2018

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Disruption of constitutive CXCR4 oligomers impairs oncogenic properties in lymphoid neoplasms

Simon Mobach1,2,3, Nick D Bergkamp1, Ziliang Ma4,5

  • 1Department of Chemistry and Pharmaceutical Sciences, Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam, Amsterdam 1081 HZ, The Netherlands.

Proceedings of the National Academy of Sciences of the United States of America
|June 11, 2025
PubMed

Insights

CXCR4 receptor oligomers play a critical role in lymphoid cancers. Disrupting these CXCR4 oligomers inhibits cancer cell growth and enhances sensitivity to venetoclax therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Chemokine receptor CXCR4 is overexpressed in cancers, contributing to disease progression and therapy resistance.
  • CXCR4 oligomerization's role in malignancies is not well understood.
  • Targeting CXCR4 may offer therapeutic benefits in cancer treatment.

Purpose of the Study:

  • To investigate the functional relevance of CXCR4 oligomerization in lymphoid cancers.
  • To determine if disrupting CXCR4 oligomers impacts cancer cell signaling and drug sensitivity.
  • To explore the therapeutic potential of targeting CXCR4 oligomers.

Main Methods:

  • Utilized a nanobody-based BRET method to study endogenous CXCR4 oligomerization.
  • Analyzed changes in cell migration, prosurvival signaling, and phosphoproteome upon oligomer disruption.
  • Assessed the effect of oligomer disruption on chronic lymphocytic leukemia (CLL) spheroid growth and venetoclax sensitivity.

Main Results:

  • CXCR4 oligomerization correlated with increased expression in lymphoid cancer cell lines.
  • Disruption of CXCR4 oligomers reduced cell migration and prosurvival signaling.
  • Oligomer disruption inhibited primary CLL spheroid growth and sensitized malignant cells to venetoclax.

Conclusions:

  • CXCR4 oligomers play a noncanonical, critical role in lymphoid neoplasms.
  • Selective targeting of CXCR4 oligomers demonstrates clinical potential for sensitizing malignant B cells to venetoclax.
  • Disrupting CXCR4 oligomers represents a promising therapeutic strategy in lymphoid malignancies.
Keywords:
CXCR4drug sensitizationleukemiareceptor oligomerization

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