title: High Erk-1 activation and Gadd45a expression as prognostic markers in high risk pediatric haemolymphoproliferative diseases.
abstract: Studies on activated cell-signaling pathways responsible for neoplastic transformation are numerous in solid tumors and in adult leukemias. Despite of positive results in the evolution of pediatric hematopoietic neoplasias, there are some high-risk subtypes at worse prognosis. The aim of this study was to asses the expression and activation status of crucial proteins involved in cell-signaling pathways in order to identify molecular alterations responsible for the proliferation and/or escape from apoptosis of leukemic blasts. The quantitative and qualitative expression and activation of Erk-1, c-Jun, Caspase8, and Gadd45a was analyzed, by immunocytochemical (ICC) and western blotting methods, in bone marrow blasts of 72 patients affected by acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (ALL) and stage IV non-Hodgkin Lymphoma (NHL). We found an upregulation of Erk-1, Caspase8, c-Jun, and Gadd45a proteins with a constitutive activation in 95.8%, 91.7%, 86.2%, 83.4% of analyzed specimens, respectively. It is worth noting that all AML patients showed an upregulation of all proteins studied and the high expression of GADD45a was associated to the lowest DFS median (p = 0.04). On univariate analysis, only Erk-1 phosphorylation status was found to be correlated with a significantly shorter 5-years DFS in all disease subgroups (p = 0.033) and the lowest DFS median in ALL/NHL subgroup (p = 0.04). Moreover, the simultaneous activation of multiple kinases, as we found for c-Jun and Erk-1 (r = 0.26; p = 0.025), might synergistically enhance survival and proliferation potential of leukemic cells. These results demonstrate an involvement of these proteins in survival of blast cells and, consequently, on relapse percentages of the different subgroups of patients.
authors.affiliation: Pediatric Oncology Service, Pediatric Department, F Fede, II University of Naples, Naples, Italy. velia.dangelo@unina2.it
authors.forename: Velia
authors.initials: V
authors.lastname: D'Angelo
authors.forename: Stefania
authors.initials: S
authors.lastname: Crisci
authors.forename: Fiorina
authors.initials: F
authors.lastname: Casale
authors.forename: Raffaele
authors.initials: R
authors.lastname: Addeo
authors.forename: Maria
authors.initials: M
authors.lastname: Giuliano
authors.forename: Elvira
authors.initials: E
authors.lastname: Pota
authors.forename: Paola
authors.initials: P
authors.lastname: Finsinger
authors.forename: Alfonso
authors.initials: A
authors.lastname: Baldi
authors.forename: Roberto
authors.initials: R
authors.lastname: Rondelli
authors.forename: Alberto
authors.initials: A
authors.lastname: Abbruzzese
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
authors.forename: Paolo
authors.initials: P
authors.lastname: Indolfi
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007223:Infant; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008232:Lymphoproliferative Disorders / Q000145:classification / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D012307:Risk Factors; D016896:Treatment Outcome; D000097642:GADD45 Proteins
chemical_list: D014408:Biomarkers, Tumor; D053181:Caspase 8; D018797:Cell Cycle Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009687:Nuclear Proteins; C439070:GADD45A protein, human; D000097642:GADD45 Proteins