Möhle R, Bautz F, Rafii S, Moore M A, Brugger W, Kanz L
Department of Medicine II, University of Tübingen, Tübingen, Germany.
Blood. 1998 Jun 15;91(12):4523-30.
The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR-4 (fusin, LESTR) are likely to be involved in the trafficking of hematopoietic progenitor and stem cells, as suggested by the reduced bone marrow hematopoiesis in SDF-1-deficient mice and the chemotactic effect of SDF-1 on CD34+ progenitor cells. Migration of leukemic cells might also depend on the expression of chemokine receptors. Therefore, we analyzed expression of CXCR-4 on mobilized normal CD34+ progenitors and leukemic cells. In addition, SDF-1-induced transendothelial migration across a bone marrow endothelial cell layer was assessed in vitro. By flow cytometry, CXCR-4 was found to be expressed in significant amounts on circulating CD34+ hematopoietic progenitor cells, including more primitive subsets (CD34+/CD38- and CD34+/Thy-1+ cells). In accordance with the immunofluorescence data, CD34+ progenitors efficiently migrated across endothelium in response to SDF-1 containing conditioned medium from the stromal cell line MS-5. Leukemic blasts (mostly CD34+) from patients with acute myeloblastic leukemia (AML) expressed variable amounts of CXCR-4, which was functionally active, as demonstrated by a positive correlation between the SDF-1-induced transendothelial migration and the cell surface density of CXCR-4 (r = 0.97). Also recombinant SDF-1beta induced migration of CXCR-4-positive leukemic blasts. The effect of both conditioned medium and recombinant SDF-1 was inhibited by a CXCR-4 blocking antibody. In contrast, CD34+ leukemic cell lines (KG1, KG1a, Kasumi-1, MOLM-1) expressed low levels or were negative for CXCR-4, and did not migrate. By reverse transcriptase-polymerase chain reaction (RT-PCR), however, basal levels of CXCR-4 mRNA were also detected in all leukemic cell lines. We conclude that CXCR-4 is expressed on CD34+ cells including more primitive, pluripotent progenitors, and may therefore play a role in the homing of hematopoietic stem cells. CXCR-4 expressed in variable amounts on primary AML leukemic cells is functionally active and may be involved in the trafficking of malignant hematopoietic cells.
趋化因子基质细胞衍生因子-1（SDF-1）及其受体CXCR-4（融合素、LESTR）可能参与造血祖细胞和干细胞的迁移，SDF-1缺陷小鼠骨髓造血功能降低以及SDF-1对CD34+祖细胞的趋化作用表明了这一点。白血病细胞的迁移可能也依赖于趋化因子受体的表达。因此，我们分析了CXCR-4在动员的正常CD34+祖细胞和白血病细胞上的表达。此外，还在体外评估了SDF-1诱导的跨骨髓内皮细胞层的内皮迁移。通过流式细胞术发现，CXCR-4在循环的CD34+造血祖细胞上大量表达，包括更原始的亚群（CD34+/CD38-和CD34+/Thy-1+细胞）。与免疫荧光数据一致，CD34+祖细胞能有效地响应来自基质细胞系MS-5的含SDF-1的条件培养基而跨内皮迁移。急性髓性白血病（AML）患者的白血病原始细胞（大多为CD34+）表达不同量的CXCR-4，其具有功能活性，SDF-1诱导的跨内皮迁移与CXCR-4的细胞表面密度呈正相关（r = 0.97）证明了这一点。重组SDF-1β也能诱导CXCR-4阳性白血病原始细胞的迁移。条件培养基和重组SDF-1的作用均被CXCR-4阻断抗体抑制。相反，CD34+白血病细胞系（KG1、KG1a、Kasumi-1、MOLM-1）表达低水平的CXCR-4或为阴性，且不迁移。然而，通过逆转录聚合酶链反应（RT-PCR），在所有白血病细胞系中也检测到了CXCR-4 mRNA的基础水平。我们得出结论，CXCR-4在包括更原始的多能祖细胞在内的CD34+细胞上表达，因此可能在造血干细胞归巢中发挥作用。原发性AML白血病细胞上不同量表达的CXCR-4具有功能活性，并可能参与恶性造血细胞的迁移。
