Acute myeloid leukaemia (AML) is the most common adult acute leukaemia with the lowest survival rate. It is characterised by a build‐up of immature myeloid cells anchored in the protective niche of the bone marrow (BM) microenvironment. The CXCL12/CXCR4 axis is central to the pathogenesis of AML as it has fundamental control over AML cell adhesion into the protective BM niche, adaptation to the hypoxic environment, cellular migration and survival. High levels of CXCR4 expression are associated with poor relapse‐free and overall survival. The CXCR4 ligand, CXCL12 (SDF‐1), is expressed by multiple cells types in the BM, facilitating the adhesion and survival of the malignant clone. Blocking the CXCL12/CXCR4 axis is an attractive therapeutic strategy providing a ‘multi‐hit’ therapy that both prevents essential survival signals and releases the AML cells from the BM into the circulation. Once out of the protective niche of the BM they would be more susceptible to destruction by conventional chemotherapeutic drugs. In this review, we disentangle the diverse roles of the CXCL12/CXCR4 axis in AML. We then describe multiple CXCR4 inhibitors, including small molecules, peptides, or monoclonal antibodies, which have been developed to date and their progress in pre‐clinical and clinical trials. Finally, the review leads us to the conclusion that there is a need for further investigation into the development of a ‘multi‐hit’ therapy that targets several signalling pathways related to AML cell adhesion and maintenance in the BM.

中文翻译：

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剖析CXCL12 / CXCR4轴在急性髓细胞性白血病中的作用。

急性髓细胞性白血病（AML）是最常见的成人急性白血病，生存率最低。其特征是未成熟的骨髓细胞的聚集锚定在骨髓（BM）微环境的保护位中。CXCL12 / CXCR4轴对AML的发病机制至关重要，因为它具有对AML细胞粘附到保护性BM利基环境，对缺氧环境的适应性，细胞迁移和存活的基本控制。高水平的CXCR4表达与不良的无复发和总体生存率相关。CXCR4配体CXCL12（SDF-1）在BM中由多种细胞类型表达，从而促进了恶性克隆的粘附和存活。阻断CXCL12 / CXCR4轴是一种引人注目的治疗策略，可提供“多次打击”疗法，既可预防必需的生存信号，又可将AML细胞从BM释放到循环系统中。一旦脱离了BM的保护性利基，它们将更易于被常规化疗药物破坏。在这篇评论中，我们解开了CXCL12 / CXCR4轴在AML中的各种作用。然后，我们描述了迄今为止已开发的多种CXCR4抑制剂，包括小分子，肽或单克隆抗体，以及它们在临床前和临床试验中的进展。最后，该综述使我们得出结论，有必要进一步研究“多重打击”疗法的发展，该疗法针对与AML细胞粘附和维持BM相关的几种信号通路。