Shear stress-mediated adhesion of acute myeloid leukemia and KG-1 cells to endothelial cells involves functional P-selectin

Abstract

Acute myeloid leukemia (AML) shows malignant behavior through the ability of immature cells to circulate in blood and to invade peripheral tissues. Whereas binding of human AML cells to endothelial cells (ECs) through E-selectin has been shown to occur using classical adhesion assays, little is known about the ability of endothelial P-selectin to support this process. We therefore characterized the ability of AML blasts and KG-1 cells to bind to endothelial selectin type ligands. Flow cytometry revealed that, in addition to various integrin adhesion receptors, AML cells regularly express the P-selectin glycoprotein ligand (PSGL)-1, a ligand for P- and E-selectin on ECs. In parallel flow chambers, AML cells both rolled and adhered to TNF-alpha pretreated human umbilical vein endothelial cells (HUVECs). Pretreatment of HUVECs with anti-P- or anti-E-selectin function blocking antibodies significantly reduced both, rolling and subsequent arrest of primary AML cells. Intravital microscopy of i.v. injected fluorescence-labeled KG-1 cells into P-selectin deficient or wild type mice confirmed a significant role of endothelial P-selectin in the binding of human primary AML cells to ECs also in vivo. Thus, the currently available data suggest a role of P- and E-selectin in coordinated circulation of AML cells. Thus, P- or E-selectin mediated adhesion of AML cells may provide a target for the development anti-leukemic therapies.