CXCR4 expression and downstream signaling have been identified as key factors in malignant hematopoiesis. Thus, up to 40% of all patients with Waldenstrom Macroglobulinemia 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.

中文翻译：

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Waldenstrom巨球蛋白血症中的天然CXCR4拮抗剂EPI-X 4抵消了CXCR4信号转导

CXCR4表达和下游信号已被确定为恶性造血的关键因素。因此，在所有华登氏巨球蛋白血症患者中，多达40％的患者携带CXCR4激活突变，导致在使用Bruton酪氨酸激酶抑制剂依鲁替尼治疗后，临床过程更加积极，结果也较差。然而，关于在造血肿瘤中抵抗CXCR4信号转导的生理机制知之甚少。最近，内源性人源肽EPI-X4被鉴定为天然CXCR4拮抗剂，可有效阻断CXCL12介导的受体内在化并抑制癌细胞向CXCL12梯度的迁移和侵袭。在这里，我们证明了EPI-X4在体外和体内均能有效损害WM细胞的生长，并阻止其向CXCL12的迁移。EPI-X4的CXCR4抑制活性伴随着MAPK信号传导和能量代谢相关基因的表达下降。值得注意的是，EPI-X4的抗WM活性可以通过合理设计表现出对CXCR4更高结合亲和力的EPI-X4衍生物来进一步增强。总之，这些数据表明，天然存在的抗CXCR4肽能够干扰WM的生长，EPI-X4的优化衍生物可能代表了一种有前途的抑制WM中促进CXCR4信号传导的方法。