Gallay Nathalie, Anani Ludovic, Lopez Adriana, Colombat Philippe, Binet Christian, Domenech Jorge, Weksler Babette B, Malavasi Fabio, Herault Olivier
INSERM ESPRI-EA3855, Université François Rabelais, Tours, France.
Cancer Res. 2007 Sep 15;67(18):8624-32. doi: 10.1158/0008-5472.CAN-07-0402.
In acute myelogenous leukemia (AML), leukemic cell-microenvironment interactions within various niches (stromal/osteoblastic or sinusoidal endothelial cell niches) have a role in leukemia cell survival and drug resistance. The AML leukemic cells express platelet/endothelial cell adhesion molecule-1 (CD31) and CD38, two adhesion molecules that could interact with microenvironmental elements, i.e., CD31 on the surface of marrow endothelial cells (CD31/CD31 and CD38/CD31 interactions) and hyaluronate (CD38/hyaluronate interactions). We report a physical association of these two antigens on the plasma membrane of myeloid leukemic cells. In this context, in vitro experiments done using interaction-blocking anti-CD31 and anti-CD38 monoclonal antibodies (CLB-HEC75 and OKT10, respectively) indicate that an excess of CD31 on the cell membrane of leukemic cells (CD31/CD38 MFI ratio >1) promotes a homotypic interaction with marrow endothelial cells, resulting in higher transendothelial migration. Conversely, an excess of CD38 (CD31/CD38 MFI ratio <1) allows leukemic cells to be entrapped within the bone marrow microenvironment through hyaluronate adhesion. The results obtained in vitro using fluorescence resonance energy transfer, co-capping, and co-immunoprecipitation experiments, and hyaluronate adhesion and transendothelial migration assays, are supported by immunophenotypic characterization of marrow leukemic cells from 78 AML patients on which CD38 expression levels were found to be positively correlated with those of CD31. Importantly, the excess of CD31 in those samples was associated with a higher peripheral WBC count. These findings indicate that bone marrow retention of AML cells depends on CD31 and CD38 coexpression levels.
在急性髓系白血病（AML）中，白血病细胞与各种龛位（基质/成骨细胞或窦状内皮细胞龛位）内的微环境相互作用在白血病细胞存活和耐药性方面发挥作用。AML白血病细胞表达血小板/内皮细胞黏附分子-1（CD31）和CD38，这两种黏附分子可与微环境成分相互作用，即骨髓内皮细胞表面的CD31（CD31/CD31和CD38/CD31相互作用）以及透明质酸（CD38/透明质酸相互作用）。我们报告了这两种抗原在髓系白血病细胞质膜上的物理关联。在此背景下，使用相互作用阻断抗CD31和抗CD38单克隆抗体（分别为CLB-HEC75和OKT10）进行的体外实验表明，白血病细胞膜上过量的CD31（CD31/CD38平均荧光强度比值>1）促进与骨髓内皮细胞的同型相互作用，导致更高的跨内皮迁移。相反，过量的CD38（CD31/CD38平均荧光强度比值<1）使白血病细胞通过透明质酸黏附被困在骨髓微环境中。使用荧光共振能量转移、共帽和共免疫沉淀实验以及透明质酸黏附和跨内皮迁移测定在体外获得的结果，得到了78例AML患者骨髓白血病细胞免疫表型特征的支持，在这些患者中发现CD38表达水平与CD31呈正相关。重要的是，那些样本中CD31的过量与更高的外周白细胞计数相关。这些发现表明AML细胞在骨髓中的滞留取决于CD31和CD38的共表达水平。
