title: Coordinated deregulation of cellular receptors, proangiogenic factors and intracellular pathways in acute myeloid leukaemia.
abstract: Different signaling routes seem to be simultaneously triggered in leukemia, with distinct and overlapping activities. To analyze if altered signals are coordinated and to evaluate their effect on this disease, we have investigated in acute myeloid leukemia samples (AML) the expression and activation status of procoagulant/proangiogenic tissue factor receptor (TF), angiogenic protein VEGF, its cell surface receptor, KDR, and two intracellular proteins involved in their regulation: extracellular regulated kinase (ERK1/2) and nuclear factor kappa-B (NFkappaB). Significantly higher mRNA and protein levels of VEGF, KDR, and TF were found in the AML samples versus controls. Enhanced ERK phosphorylation and NFkappaB activation in most AML samples were also found. In vitro MEK/ERK and NFkappaB-binding activity blockade suppressed the constitutive expression of TF, VEGF, and KDR. Anti-TF antibody treatment significantly suppressed VEGF and KDR expression as well as ERK activation, suggesting that TF expressed by AML cells may be both a regulatory target and a mediator of tumor-associated angiogenesis. Patients showing parallel activation of the studied proteins trended to exhibit higher incidence of fatal outcome. Our results show a coordinated deregulation of cellular receptors, proangiogenic factors, and intracellular pathways in leukemia cells, which may help to design mechanism-based combinations of single transduction-related therapies.
authors.affiliation: Unidad de Investigación Hospital Reina Sofía, Córdoba, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Barbarroja
authors.forename: Luis
authors.initials: L
authors.lastname: Arístides-Torres
authors.forename: Vanessa
authors.initials: V
authors.lastname: Hernandez
authors.forename: Carmen
authors.initials: C
authors.lastname: Martín
authors.forename: Gabriel
authors.initials: G
authors.lastname: Dorado
authors.forename: Antonio
authors.initials: A
authors.lastname: Torres
authors.forename: Francisco
authors.initials: F
authors.lastname: Velasco
authors.forename: Chary
authors.initials: C
authors.lastname: Lopez-Pedrera
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042501:Angiogenic Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002675:Child, Preschool; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D013925:Thromboplastin / Q000037:antagonists & inhibitors / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
chemical_list: D042501:Angiogenic Proteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D013925:Thromboplastin; D040301:Vascular Endothelial Growth Factor Receptor-2; D048049:Extracellular Signal-Regulated MAP Kinases