title: Mammalian target of rapamycin (mTOR) activity dependent phospho-protein expression in childhood acute lymphoblastic leukemia (ALL).
abstract: Modern treatment strategies have improved the prognosis of childhood ALL; however, treatment still fails in 25-30% of patients. Further improvement of treatment may depend on the development of targeted therapies. mTOR kinase, a central mediator of several signaling pathways, has recently attracted remarkable attention as a potential target in pediatric ALL. However, limited data exists about the activity of mTOR. In the present study, the amount of mTOR activity dependent phospho-proteins was characterized by ELISA in human leukemia cell lines and in lymphoblasts from childhood ALL patients (n = 49). Expression was measured before and during chemotherapy and at relapses. Leukemia cell lines exhibited increased mTOR activity, indicated by phospho-S6 ribosomal protein (p-S6) and phosphorylated eukaryotic initiation factor 4E binding protein (p-4EBP1). Elevated p-4EBP1 protein levels were detected in ALL samples at diagnosis; efficacy of chemotherapy was followed by the decrease of mTOR activity dependent protein phosphorylation. Optical density (OD) for p-4EBP1 (ELISA) was significantly higher in patients with poor prognosis at diagnosis, and in the samples of relapsed patients. Our results suggest that measuring mTOR activity related phospho-proteins such as p-4EBP1 by ELISA may help to identify patients with poor prognosis before treatment, and to detect early relapses. Determining mTOR activity in leukemic cells may also be a useful tool for selecting patients who may benefit from future mTOR inhibitor treatments.
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Karolina
authors.initials: K
authors.lastname: Nemes
authors.forename: Anna
authors.initials: A
authors.lastname: Sebestyén
authors.forename: Agnes
authors.initials: A
authors.lastname: Márk
authors.forename: Melinda
authors.initials: M
authors.lastname: Hajdu
authors.forename: István
authors.initials: I
authors.lastname: Kenessey
authors.forename: Tamás
authors.initials: T
authors.lastname: Sticz
authors.forename: Eszter
authors.initials: E
authors.lastname: Nagy
authors.forename: Gábor
authors.initials: G
authors.lastname: Barna
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Váradi
authors.forename: Gábor
authors.initials: G
authors.lastname: Kovács
authors.forename: László
authors.initials: L
authors.lastname: Kopper
authors.forename: Monika
authors.initials: M
authors.lastname: Csóka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000293:Adolescent; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004357:Drug Synergism; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D015999:Multivariate Analysis; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D011499:Protein Processing, Post-Translational; D012372:ROC Curve; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus