Olsnes A M, Hatfield K J, Bruserud Ø
Division of Hematology, Department of Medicine, Haukeland University Hospital and The University of Bergen, Bergen, Norway.
J BUON. 2009 Sep;14 Suppl 1:S131-40.
The chemokine family consists of approximately 50 small (8-14 kDa), basic proteins that are expressed and released by a wide range of normal and malignant cells. Most chemokines act through heptahelical transmembrane G protein- coupled receptors. Based on their molecular structure these cytokines are divided into the two major subgroups CCL and CXCL chemokines that bind to CCR or CXCR receptors respectively. Primary human acute myelogenous leukemia (AML) cells show constitutive release of a wide range of chemokines, but the chemokine release profile differs between patients. Among the commonly expressed chemokines are proangiogenic CXCL8, antiangiogenic CXCL4/9-11 and several leukocyte-chemotactic chemokines. Systemic serum levels of leukocyte-chemotactic chemokines depend both on patient age, disease status, the chemotherapy regimen and development of complicating infections. The local chemokine network in human AML is probably further modulated by the hypoxic bone marrow microenvironment and the local release of chemokines by nonleukemic bone marrow stromal cells. Usually primary AML cells also express several chemokine receptors. Specific chemokine inhibitors are now being developed, including chemokine-neutralizing or receptor-blocking antibodies, antisense strategies, receptor-blocking small molecules or inhibitors of downstream signaling. The use of CXCR4-antagonists for mobilization of peripheral blood stem cells has been documented in several clinical studies. Although animal studies suggest that chemokine inhibition also may become useful in the treatment of graft versus host disease, the possible use of chemokine-targeting therapy for other indications than stem cell mobilization requires further studies.
趋化因子家族由大约50种小（8 - 14 kDa）的碱性蛋白质组成，这些蛋白质由多种正常细胞和恶性细胞表达并释放。大多数趋化因子通过七螺旋跨膜G蛋白偶联受体发挥作用。基于其分子结构，这些细胞因子被分为两个主要亚组，即CCL趋化因子和CXCL趋化因子，它们分别与CCR或CXCR受体结合。原发性人类急性髓性白血病（AML）细胞可组成性释放多种趋化因子，但不同患者的趋化因子释放谱有所不同。常见表达的趋化因子包括促血管生成的CXCL8、抗血管生成的CXCL4/9 - 11以及几种白细胞趋化趋化因子。白细胞趋化趋化因子的全身血清水平既取决于患者年龄、疾病状态、化疗方案，也取决于并发症感染的发生情况。人类AML中的局部趋化因子网络可能会进一步受到缺氧骨髓微环境以及非白血病骨髓基质细胞局部释放趋化因子的调节。通常原发性AML细胞也表达多种趋化因子受体。目前正在开发特异性趋化因子抑制剂，包括趋化因子中和或受体阻断抗体、反义策略、受体阻断小分子或下游信号抑制剂。在多项临床研究中已证实使用CXCR4拮抗剂动员外周血干细胞。尽管动物研究表明趋化因子抑制在移植物抗宿主病的治疗中可能也有用，但除了干细胞动员之外，趋化因子靶向治疗在其他适应症中的可能应用还需要进一步研究。
