CXCL12 Dimers Stimulate Durable Receptor Desensitization
Acute myelogenous leukemia (AML) is a heterogenous malignancy of adults and children characterized by clonal expansion of immature myeloid blast cells with resulting bone marrow failure and ineffective erythropoiesis. The CXCL12-CXCR4 chemokine axis has been suggested as an attractive treatment avenue in leukemia as the bone marrow is enriched in CXCL12 producing cells that functionally maintain AML populations within the protective bone marrow niche, allowing the tumors to avoid or overcome common cytotoxic chemotherapies. While AMD3100, a clinically available inhibitor of CXCR4 known by the trade name Plerixafor, is used clinically to mobilize hematopoietic stem cells out of the bone marrow phase I/II clinical trials combining AMD3100 with a variety of chemotherapy regimens in adults with AML have found little to no clinical benefit.
Figure. Internalization of fluorescently-labeled AF647 CXCL12 wild-type, monomer, or dimer ligands. Drouillard et al. Sci Report, 2025. PMCID: PMC12284246
In a recent publication in a Scientific Reports manuscript, Drouillard and colleagues used rationally designed and engineered variants of the chemokine CXCL12 to uncover a role for dimer locked CXCL12 in prolonged and more potent ligand-induced internalization of CXCR4. Using fluorescently labeled CXCL12, Drouillard demonstrated that dimeric ligand stimulated CXCR4 internalization that was faster and more durable over time than either monomeric CXCL12 or AMD3100 (Figure). Mechanistically, dimer-induced CXCR4 internalization was independent of G protein signaling or ß-arrestin recruitment. Given that plerixafor and other CXCR4 antagonists induce pharmacodynamic tolerance, with the antagonist stimulated upregulation of CXCR4 expression, it remains possible that CXCL12 locked dimers may provide an alternative pharmacologic approach to stimulate the mobilization out of the bone marrow and increase the tumors sensitivity to cytotoxic therapies.
Engineered variants and fluorescently labeled CXCL12 were purchased from Protein Foundry and show utility in both cell culture and mouse models of disease.
Drouillard D, Halyko M, Cinquegrani E, Poimenidou M, Emosivbe M, McAllister D, Peterson FC, Marchese A, Dwinell MB. CXCL12 chemokine dimer signaling modulates acute myelogenous leukemia cell migration through altered receptor internalization. Sci Rep. 2025 Jul 22;15(1):26625. doi: 10.1038/s41598-025-12005-7. PMID: 40696056; PMCID: PMC12284246.
