Article: article from journal or magazin.
Endothelial cell activation by myeloblasts: molecular mechanisms of leukostasis and leukemic cell dissemination
Journal Article Research Support, Non-U.S. Gov't --- Old month value: Apr 1
Leukostasis and tissue infiltration by leukemic cells are poorly understood life-threatening complications of acute leukemia. This study has tested the 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 the French-American-British Cooperative Group expressed various amounts of adhesion receptors, including CD11a, b, c/CD18, CD49d, e, f/CD29, CD54, sCD15, and L-selectin. The presence of functional adhesion receptors was evaluated 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 showed that multiple adhesion receptors--including L-selectin, E-selectin, VCAM-1, and CD11/CD18--were involved in blast cell adhesion to TNF-alpha-activated endothelium. Leukemic cells were then cocultured at 37 degrees C on unactivated 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. Additional 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 expressed 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 pathophysiology of leukostasis and tissue infiltration by leukemic blast cells. (Blood. 2001;97:2121-2129)
Antigens, CD/*biosynthesis/genetics Antigens, CD15/biosynthesis/genetics Antigens, CD18/biosynthesis/genetics Antigens, CD29/biosynthesis/genetics Cell Adhesion Cell Adhesion Molecules/*biosynthesis/genetics Cells, Cultured Coculture Techniques E-Selectin/biosynthesis/genetics Endothelium, Vascular/*metabolism/pathology *Gene Expression Regulation, Leukemic Humans Integrin alpha4 Integrin alpha5 Integrin alpha6 Integrin alphaXbeta2/biosynthesis/genetics Intercellular Adhesion Molecule-1/biosynthesis/genetics Interleukin-1/*secretion L-Selectin/biosynthesis/genetics Leukemia, Myeloid/genetics/metabolism/*pathology Leukemic Infiltration/genetics/*metabolism Leukostasis/genetics/*metabolism Lymphocyte Function-Associated Antigen-1/biosynthesis/genetics Macrophage-1 Antigen/biosynthesis/genetics Neoplasm Proteins/biosynthesis/genetics/*secretion Receptors, Lymphocyte Homing/biosynthesis/genetics Tumor Cells, Cultured Tumor Necrosis Factor-alpha/*secretion Tumor Stem Cells/cytology/*secretion Vascular Cell Adhesion Molecule-1/biosynthesis/genetics
Web of science
Last modification date