Biokine Therapeutics Ltd., Science Park, Ness Ziona, Israel.
Br J Haematol. 2013 Oct;163(2):248-59. doi: 10.1111/bjh.12501. Epub 2013 Aug 1.
Platelets are the terminal differentiation product of megakaryocytes (MKs). Cytokines, such as thrombopoietin (TPO), are known to influence different steps in MK development; however, the complex differentiation and platelet localization processes are not fully understood. MKs express the receptor CXCR4 and have been shown to migrate in response to CXCL12 and to increase their platelet production. In this study, we studied the role of CXCR4 in platelet production with the high affinity CXCR4 antagonist, BKT140. Single and sequential administration of BKT140 significantly increased the number of MKs and haematopoietic progenitors (HPCs) within the bone marrow (BM). Increased megakaryopoiesis was associated with increased platelet production. Single and sequential administration of BKT140 also increased the number of HPCs in the blood. In a model of 5-fluorouracil-induced thrombocytopenia, BKT140 significantly reduced the severity and duration of thrombocytopenia and cytopenia when administered before and after chemotherapy. Our results demonstrated that the CXCR4 antagonist, BKT140, mediated unique beneficial effects by stimulating megakaryopoiesis and platelet production. These results provide evidence for the possible therapeutic use of BKT140 for modulating platelet numbers in thrombocytopenic conditions.
血小板是巨核细胞（MKs）的终末分化产物。已知细胞因子，如血小板生成素（TPO），会影响 MK 发育的不同阶段；然而，复杂的分化和血小板定位过程尚未完全了解。MK 表达受体 CXCR4，并已被证明可以响应 CXCL12 迁移并增加其血小板生成。在这项研究中，我们使用高亲和力 CXCR4 拮抗剂 BKT140 研究了 CXCR4 在血小板生成中的作用。BKT140 的单次和序贯给药显著增加了骨髓（BM）中 MK 和造血祖细胞（HPC）的数量。巨核细胞生成增加与血小板生成增加有关。BKT140 的单次和序贯给药也增加了血液中 HPC 的数量。在 5-氟尿嘧啶诱导的血小板减少症模型中，BKT140 在化疗前后给药可显著减轻血小板减少症和细胞减少症的严重程度和持续时间。我们的结果表明，CXCR4 拮抗剂 BKT140 通过刺激巨核细胞生成和血小板生成产生独特的有益作用。这些结果为 BKT140 在血小板减少症情况下调节血小板数量的可能治疗用途提供了证据。
