Journal article
CXCL12 chemokine dimer signaling modulates acute myelogenous leukemia cell migration through altered receptor internalization
Scientific reports, Vol.15(1), 26625
07/22/2025
DOI: 10.1038/s41598-025-12005-7
PMCID: PMC12284246
PMID: 40696056
Abstract
Acute myeloid leukemia (AML) is a malignancy of immature myeloid blast cells with stem-like and chemoresistant cells being retained in the bone marrow through CXCL12-CXCR4 signaling. Current CXCR4 inhibitors that mobilize AML cells into the bloodstream have failed to improve patient survival, likely reflecting persistent chemokine receptor localization on target cells. Here we characterize the signaling properties of CXCL12-locked dimer (CXCL12-LD), a bioengineered variant of the naturally occurring oligomer of CXCL12. CXCL12-LD, in contrast to wild-type or locked monomer variants, was unable to induce chemotaxis in AML cells. CXCL12-LD binding to CXCR4 decreased G protein, β-arrestin, and intracellular calcium mobilization signaling pathways, and indicated the locked dimer is a partial agonist of CXCR4. Despite these partial agonist properties, CXCL12-LD increased CXCR4 internalization compared to wild-type and monomeric CXCL12. Analysis of a previously published AML transcriptomic data showed CXCR4 positive AML cells co-express genes involved in survival, proliferation, and maintenance of a blast-like state. The CXCL12-LD partial agonist effectively mobilized stem cells into the bloodstream in mice suggesting a potential role for their use in targeting CXCR4. Together, our results suggest that enhanced internalization by CXCL12-LD partial agonist can avoid pharmacodynamic tolerance and may identify new avenues to better target GPCRs.
Details
- Title: Subtitle
- CXCL12 chemokine dimer signaling modulates acute myelogenous leukemia cell migration through altered receptor internalization
- Creators
- Donovan Drouillard - Medical College of WisconsinMichael Halyko - Medical College of WisconsinElizabeth Cinquegrani - Medical College of WisconsinMaria Poimenidou - Medical College of WisconsinMiracle Emosivbe - Medical College of WisconsinDonna McAllister - Medical College of WisconsinFrancis C Peterson - Medical College of WisconsinAdriano Marchese - Medical College of WisconsinMichael B Dwinell - Medical College of Wisconsin
- Resource Type
- Journal article
- Publication Details
- Scientific reports, Vol.15(1), 26625
- DOI
- 10.1038/s41598-025-12005-7
- PMID
- 40696056
- PMCID
- PMC12284246
- NLM abbreviation
- Sci Rep
- ISSN
- 2045-2322
- eISSN
- 2045-2322
- Publisher
- NATURE PORTFOLIO
- Grant note
- National Cancer Institute: R01 CA226279, F30 CA291095 National Institutes of Health Training Grant from the National Institute of General Medical Sciences: T32 GM080202
This work is supported in part by grants from the National Cancer Institute R01 CA226279 to M.B.D and philanthropic support from the Hanis-Stepka-Rettig Endowed Chair in Cancer Research, and the Bobbie Nick Voss Charitable Foundation. The content is solely the responsibility of the author(s) and does not necessarily represent the official views of the NIH. D.D. is a member of the Medical Scientist Training Program at the Medical College of Wisconsin, which is supported in part by National Institutes of Health Training Grant T32 GM080202 from the National Institute of General Medical Sciences. D.D is supported in part by the grant from the National Cancer Institute F30 CA291095. The content is solely the responsibility of the author(s) and does not necessarily represent the official views of the National Institutes of Health.
- Language
- English
- Date published
- 07/22/2025
- Academic Unit
- Stead Family Department of Pediatrics; Hematology/Oncology
- Record Identifier
- 9984865435502771
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