Targeting of CXCR4 by the Naturally Occurring CXCR4 Antagonist EPI-X4 in Waldenström’s Macroglobulinemia
1
Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital Ulm, 89081 Ulm, Germany
2
Institute of Molecular Virology, Ulm University Medical Center, 89081 Ulm, Germany
3
Institute for Medical Virology and Epidemiology of Viral Diseases, University Hospital Tübingen, 72076 Tübingen, Germany
4
Special Centre for Molecular Medicine, Jawaharlal Nehru University, Delhi 110067, India
5
Department of Virology, Paul-Ehrlich-Institute, 63225 Langen, Germany
6
Department of Pediatrics and Adolescent Medicine, University Hospital Ulm, 89081 Ulm, Germany
7
Bing Center for Waldenström’s Macroglobulinemia, Boston, MA 02215, USA
8
Department of Internal Medicine III, University Hospital Ulm, 89081 Ulm, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Aldo M. Roccaro
Cancers 2021, 13(4), 826; https://doi.org/10.3390/cancers13040826
Received: 7 December 2020
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Revised: 5 February 2021
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Accepted: 11 February 2021
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Published: 16 February 2021
(This article belongs to the Section Cancer Pathophysiology)
Simple Summary
Waldenström’s Macroglobulinemia is a B-cell lymphoma, for which no curative established treatment exists. One of the drivers of tumor growth in this disease are genetic alterations of the gene CXCR4, which can be found in up to 40% of patients with this disease. Patients with CXCR4 mutations typically have a more aggressive disease. In this article we provide evidence that a naturally occurring peptide, called EPIX4 and its optimized derivatives bind to CXCR4 on Waldenström’s macroglobulinemia cells and are able to impair growth of these lymphoma cells in mice. These data highlight that there are natural mechanisms which counteract CXCR4 driven lymphoma growth. In addition, they underline that optimizing naturally occurring CXCR4 antagonists can potentially lead to the development of novel therapies in Waldenström’s macroglobulinemia, particular in patients with CXCR4 alterations affected by a more aggressive course of disease.
CXCR4 expression and downstream signaling have been identified as key factors in malignant hematopoiesis. Thus, up to 40% of all patients with Waldenström’s macroglobulinemia (WM) carry an activating mutation of CXCR4 that leads to a more aggressive clinical course and inferior outcome upon treatment with the Bruton’s tyrosine kinase inhibitor ibrutinib. Nevertheless, little is known about physiological mechanisms counteracting CXCR4 signaling in hematopoietic neoplasms. Recently, the endogenous human peptide EPI-X4 was identified as a natural CXCR4 antagonist that effectively blocks CXCL12-mediated receptor internalization and suppresses the migration and invasion of cancer cells towards a CXCL12 gradient. Here, we demonstrate that EPI-X4 efficiently binds to CXCR4 of WM cells and decreases their migration towards CXCL12. The CXCR4 inhibitory activity of EPI-X4 is accompanied by reduced expression of genes involved in MAPK signaling and energy metabolism. Notably, the anti-WM activity of EPI-X4 could be further augmented by the rational design of EPI-X4 derivatives showing higher binding affinity to CXCR4. In summary, these data demonstrate that a naturally occurring anti-CXCR4 peptide is able to interfere with WM cell behaviour, and that optimized derivatives of EPI-X4 may represent a promising approach in suppressing growth promoting CXCR4 signaling in WM.
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Keywords:
Waldenström’s Macroglobulinemia; CXCR4; EPI-X4; CXCR4 antagonist
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MDPI and ACS Style
Kaiser, L.M.; Harms, M.; Sauter, D.; Rawat, V.P.S.; Glitscher, M.; Hildt, E.; Tews, D.; Hunter, Z.; Münch, J.; Buske, C. Targeting of CXCR4 by the Naturally Occurring CXCR4 Antagonist EPI-X4 in Waldenström’s Macroglobulinemia. Cancers 2021, 13, 826. https://doi.org/10.3390/cancers13040826
AMA Style
Kaiser LM, Harms M, Sauter D, Rawat VPS, Glitscher M, Hildt E, Tews D, Hunter Z, Münch J, Buske C. Targeting of CXCR4 by the Naturally Occurring CXCR4 Antagonist EPI-X4 in Waldenström’s Macroglobulinemia. Cancers. 2021; 13(4):826. https://doi.org/10.3390/cancers13040826
Chicago/Turabian StyleKaiser, Lisa M., Mirja Harms, Daniel Sauter, Vijay P.S. Rawat, Mirco Glitscher, Eberhard Hildt, Daniel Tews, Zachary Hunter, Jan Münch, and Christian Buske. 2021. "Targeting of CXCR4 by the Naturally Occurring CXCR4 Antagonist EPI-X4 in Waldenström’s Macroglobulinemia" Cancers 13, no. 4: 826. https://doi.org/10.3390/cancers13040826
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