Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
Leukemia. 2012 Jun;26(6):1301-12. doi: 10.1038/leu.2011.369. Epub 2012 Jan 6.
CD49d and CD38 are independent negative prognostic markers in chronic lymphocytic leukemia (CLL). Their associated expression marks a disease subset with a highly aggressive clinical course. Here, we demonstrate a constitutive physical association between the CD49d/CD29 integrin complex and CD38 in primary CLL cells and B-cell lines by (i) cocapping, (ii) coimmunoprecipitation and (iii) cell adhesion experiments using CD49d-specific substrates (vascular-cell adhesion molecule-1 or CS-1/H89 fibronectin fragments). The role of CD38 in CD49d-mediated cell adhesion was studied in CD49d(+)CD38(+) and CD49d(+)CD38(-) primary CLL cells, and confirmed using CD38 transfectants of the originally CD49d(+)CD38(-) CLL-derived cell line Mec-1. Results indicate that CD49d(+)CD38(+) cells adhered more efficiently onto CD49d-specific substrates than CD49d(+)CD38(-) cells (P < 0.001). Upon adhesion, CD49d(+)CD38(+) cells underwent distinctive changes in cell shape and morphology, with higher levels of phosphorylated Vav-1 than CD49d(+)CD38(-) cells (P = 0.0006) and a more complex distribution of F-actin to the adhesion sites. Lastly, adherent CD49d(+)CD38(+) cells were more resistant to serum-deprivation-induced (P < 0.001) and spontaneous (P = 0.03) apoptosis than the CD49d(+)CD38(-) counterpart. Altogether, our results point to a direct role for CD38 in enhancing CD49d-mediated adhesion processes in CLL, thus providing an explanation for the negative clinical impact exerted by these molecules when coexpressed in neoplastic cells.
CD49d 和 CD38 是慢性淋巴细胞白血病（CLL）的独立负预后标志物。它们的共同表达标志着具有高度侵袭性临床病程的疾病亚群。在这里，我们通过（i）共帽，（ii）共免疫沉淀和（iii）使用 CD49d 特异性底物（血管细胞黏附分子-1 或 CS-1/H89 纤维连接蛋白片段）的细胞黏附实验，证明了原发性 CLL 细胞和 B 细胞系中 CD49d/CD29 整联蛋白复合物与 CD38 之间的组成性关系。在 CD49d(+)CD38(+)和 CD49d(+)CD38(-)原发性 CLL 细胞中研究了 CD38 在 CD49d 介导的细胞黏附中的作用，并使用最初 CD49d(+)CD38(-)的 CLL 衍生细胞系 Mec-1 的 CD38 转染体进行了验证。结果表明，CD49d(+)CD38(+)细胞比 CD49d(+)CD38(-)细胞更有效地黏附在 CD49d 特异性底物上（P < 0.001）。在黏附后，CD49d(+)CD38(+)细胞发生了明显的细胞形状和形态变化，与 CD49d(+)CD38(-)细胞相比，磷酸化 Vav-1 的水平更高（P = 0.0006），并且 F-肌动蛋白向黏附部位的分布更复杂。最后，与 CD49d(+)CD38(-)细胞相比，黏附的 CD49d(+)CD38(+)细胞对血清剥夺诱导的（P < 0.001）和自发的（P = 0.03）凋亡更具抗性。总的来说，我们的结果表明 CD38 在增强 CLL 中 CD49d 介导的黏附过程中具有直接作用，从而为这些分子在肿瘤细胞中共同表达时产生的负面临床影响提供了解释。
