The PI3-Kinase Delta Inhibitor Idelalisib (GS-1101) Targets Integrin-Mediated Adhesion of Chronic Lymphocytic Leukemia (CLL) Cell to Endothelial and Marrow Stromal Cells

CLL cell trafficking between blood and tissue compartments is an integral part of the disease process. Idelalisib, a phosphoinositide 3-kinase delta (PI3Kδ) inhibitor causes rapid lymph node shrinkage, along with an increase in lymphocytosis, prior to inducing objective responses in CLL patients. This characteristic activity presumably is due to CLL cell redistribution from tissues into the blood, but the underlying mechanisms are not fully understood. We therefore analyzed idelalisib effects on CLL cell adhesion to endothelial and bone marrow stromal cells (EC, BMSC). We found that idelalisib inhibited CLL cell adhesion to EC and BMSC under static and shear flow conditions. TNFα-induced VCAM-1 (CD106) expression in supporting layers increased CLL cell adhesion and accentuated the inhibitory effect of idelalisib. Co-culture with EC and BMSC also protected CLL from undergoing apoptosis, and this EC- and BMSC-mediated protection was antagonized by idelalisib. Furthermore, we demonstrate that CLL cell adhesion to EC and VLA-4 (CD49d) resulted in the phosphorylation of Akt, which was sensitive to inhibition by idelalisib. These findings demonstrate that idelalisib interferes with integrin-mediated CLL cell adhesion to EC and BMSC, providing a novel mechanism to explain idelalisib-induced redistribution of CLL cells from tissues into the blood.

慢性淋巴细胞白血病（CLL）细胞在血液与组织间隙间的转运是疾病进程不可或缺的组成部分。艾代拉利司（Idelalisib）作为一种磷酸肌醇3-激酶δ（PI3Kδ）抑制剂，可在慢性淋巴细胞白血病患者获得客观缓解前，快速引发淋巴结缩小，并伴随淋巴细胞增多症。该特征性活性推测源于CLL细胞从组织向血液的重分布，但其潜在机制尚未完全阐明。为此，我们分析了艾代拉利司对CLL细胞黏附于内皮细胞与骨髓基质细胞（EC、BMSC）的影响。研究发现，在静态及剪切流条件下，艾代拉利司均可抑制CLL细胞与EC、BMSC的黏附。肿瘤坏死因子α（TNFα）诱导支持层表达的血管细胞黏附分子1（VCAM-1，CD106）可增强CLL细胞黏附，并强化艾代拉利司的抑制作用。与EC、BMSC共培养还可保护CLL细胞免于凋亡，而艾代拉利司可拮抗这种由EC与BMSC介导的保护作用。此外，我们证实CLL细胞通过极晚抗原4（VLA-4，CD49d）黏附于内皮细胞，可引发Akt的磷酸化，且该过程可被艾代拉利司抑制。上述研究结果表明，艾代拉利司可干扰整合素介导的CLL细胞与EC、BMSC的黏附，为解释艾代拉利司诱导CLL细胞从组织向血液重分布的现象提供了全新机制。