Endothelial cell activation by myeloblasts: molecular mechanisms of leukostasis and leukemic cell dissemination

Leukostasis and tissue infiltration by leukemic cells are poorly understood life-threatening complications of acute leukemia. This study has tested th e hypothesis that adhesion receptors and cytokines secreted by blast cells play central roles in these reactions. Immunophenotypic studies showed that acute myeloid leukemia (AML) cells (n = 78) of the M0 to M5 subtypes of th e French-American-British Cooperative Group expressed various amounts of ad hesion receptors, including CD11a, b, c/CD18, CD49d, e, f/CD29, CD54, sCD15 , and L-selectin, The presence of functional adhesion receptors was evaluat ed using a nonstatic adhesion assay. The number of blast cells attached to unactivated endothelium increased by 7 to 31 times after a 6-hour exposure of endothelium to tumor necrosis factor (TNF)-alpha. Inhibition studies sho wed that multiple adhesion receptors-including L-selectin, E-selectin, VCAM -1, and CD11/CD18-were involved in blast cell adhesion to TNF-alpha -activa ted endothelium. Leukemic cells were then cocultured at 37 degreesC on unac tivated endothelial cell monolayers for time periods up to 24 hours, A time -dependent increase in the number of blasts attached to the endothelium and a concomitant induction of ICAM-1, VCAM-1, and E-selectin were observed. A dditional experiments revealed that endothelial cell activation by leukemic myeloblasts was caused by cytokine secretion by blast cells, in particular TNF-alpha and IL-1 beta, and direct contacts between adhesion receptors ex pressed by blast cells and endothelial cells. Thus, leukemic cells have the ability to generate conditions that promote their own adhesion to vascular endothelium, a property that may have important implications for the patho physiology of leukostasis and tissue infiltration by leukemic blast cells.