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 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)
Division and Central Laboratory of Hematology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
A
A
Stucki
A S
AS
Rivier
M
M
Gikic
N
N
Monai
M
M
Schapira
O
O
Spertini
D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D018821:CD18 Antigens / Q000096:biosynthesis / Q000235:genetics; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D018920:Coculture Techniques; D019040:E-Selectin / Q000096:biosynthesis / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D039441:Integrin alpha4; D039482:Integrin alpha5; D039503:Integrin alpha6; D016167:Integrin alphaXbeta2 / Q000096:biosynthesis / Q000235:genetics; D019012:Integrin beta1 / Q000096:biosynthesis / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D007375:Interleukin-1 / Q000378:metabolism*; D019041:L-Selectin / Q000096:biosynthesis / Q000235:genetics; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017254:Leukemic Infiltration / Q000235:genetics / Q000378:metabolism*; D018921:Leukostasis / Q000235:genetics / Q000378:metabolism*; D016256:Lewis X Antigen / Q000096:biosynthesis / Q000235:genetics; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis / Q000235:genetics; D016177:Macrophage-1 Antigen / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
D015703:Antigens, CD; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D039482:Integrin alpha5; D039503:Integrin alpha6; D016167:Integrin alphaXbeta2; D019012:Integrin beta1; D007375:Interleukin-1; D016256:Lewis X Antigen; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D009363:Neoplasm Proteins; D016201:Receptors, Lymphocyte Homing; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin; D039441:Integrin alpha4