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• W3104735946 abstract "Abstract 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 impairs growth of WM cells in vitro and in vivo and blocks their migration towards CXCL12. The CXCR4 inhibitory activity of EPI-X4 is accompanied by decreased 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 growth, and that optimized derivatives of EPI-X4 may represent a promising approach in suppressing growth promoting CXCR4 signaling in WM." @default.
• W3104735946 created "2020-11-23" @default.
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• W3104735946 date "2020-10-19" @default.
• W3104735946 modified "2023-09-27" @default.
• W3104735946 title "Targeting of CXCR4 by the naturally occurring CXCR4 antagonist EPI-X 4 in Waldenström’s Macroglobulinemia" @default.
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• W3104735946 doi "https://doi.org/10.1101/2020.10.19.344812" @default.
• W3104735946 hasPublicationYear "2020" @default.
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