title: Potential role of AKT/mTOR signalling proteins in hairy cell leukaemia: association with BRAF/ERK activation and clinical outcome.
abstract: The potential role of AKT/mTOR signalling proteins and its association with the Raf-MEK-ERK pathway was investigated in hairy cell leukaemia (HCL). BRAFV600E expression and activated forms of AKT, mTOR, ERK1/2, p70S6k and 4E-BP1 were immunohistochemically assessed in 77 BM biopsies of HCL patients and correlated with clinicopathological and BM microvascular characteristics, as well as with c-Caspase-3 levels in hairy cells. Additionally, we tested rapamycin treatment response of BONNA-12 wild-type cells or transfected with BRAFV600E. Most HCL cases expressed p-p70S6K and p-4E-BP1 but not p-mTOR, being accompanied by p-ERK1/2 and p-AKT. AKT/mTOR activation was evident in BONNA-12 cells irrespective of the presence of BRAFV600E mutation and was implicated in cell proliferation enhancement. In multivariate analysis p-AKT/p-mTOR/p-4E-BP1 overexpression was an adverse prognostic factor for time to next treatment conferring earlier relapse. When p-AKT, p-mTOR and p-4E-BP1 were examined separately only p-4E-BP1 remained significant. Our findings indicate that in HCL, critical proteins up- and downstream of mTOR are activated. Moreover, the strong associations with Raf-MEK-ERK signalling imply a possible biologic interaction between these pathways. Most importantly, expression of p-4E-BP1 alone or combined with p-AKT and p-mTOR is of prognostic value in patients with HCL.
authors.affiliation: Department of Pathology, University of Athens, Medical School, Greece.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Lakiotaki
authors.affiliation: Department of Pathology, University of Athens, Medical School, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Levidou
authors.affiliation: Department of Haematology and Bone Marrow Transplantation, University of Athens, Medical School, Greece.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Angelopoulou
authors.affiliation: Department of Biological Chemistry, University of Athens, Medical School, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Adamopoulos
authors.affiliation: Department of Haematology, Athens Medical Centre, Psychikon Branch, Greece.
authors.forename: Gerassimos
authors.initials: G
authors.lastname: Pangalis
authors.affiliation: Department of Pathology, University of Athens, Medical School, Greece.|Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: George
authors.initials: G
authors.lastname: Rassidakis
authors.affiliation: Department of Haematology and Bone Marrow Transplantation, University of Athens, Medical School, Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Vassilakopoulos
authors.affiliation: Department of Haematology and Bone Marrow Transplantation, University of Athens, Medical School, Greece.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gainaru
authors.affiliation: Department of Haematology and Bone Marrow Transplantation, University of Athens, Medical School, Greece.
authors.forename: Pagona
authors.initials: P
authors.lastname: Flevari
authors.affiliation: Department of Haematology, Athens Medical Centre, Psychikon Branch, Greece.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Sachanas
authors.affiliation: Department of Pathology, University of Athens, Medical School, Greece.
authors.forename: Angelica A
authors.initials: AA
authors.lastname: Saetta
authors.affiliation: Department of Pathology, University of Athens, Medical School, Greece.
authors.forename: Athanasia
authors.initials: A
authors.lastname: Sepsa
authors.affiliation: Department of Haematology, Athens Medical Centre, Psychikon Branch, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Moschogiannis
authors.affiliation: Department of Haematology, University of Crete, Heraklion, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Kalpadakis
authors.affiliation: Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Tsesmetzis
authors.affiliation: Department of Pathology, University of Athens, Medical School, Greece.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Milionis
authors.affiliation: Department of Pathology, University of Athens, Medical School, Greece.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Chatziandreou
authors.affiliation: Department of Pathology, University of Athens, Medical School, Greece.
authors.forename: Irene
authors.initials: I
authors.lastname: Thymara
authors.affiliation: 1st Department of Propaedeutic Internal Medicine, University of Athens, Medical School, Greece.
authors.forename: Panayiotis
authors.initials: P
authors.lastname: Panayiotidis
authors.affiliation: Department of Haematology and Bone Marrow Transplantation, University of Athens, Medical School, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Dimopoulou
authors.affiliation: Department of Haematology and Bone Marrow Transplantation, University of Athens, Medical School, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Plata
authors.affiliation: Department of Haematology and Bone Marrow Transplantation, University of Athens, Medical School, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Konstantopoulos
authors.affiliation: Department of Pathology, University of Athens, Medical School, Greece.
authors.forename: Efstratios
authors.initials: E
authors.lastname: Patsouris
authors.affiliation: Department of Biological Chemistry, University of Athens, Medical School, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Piperi
authors.affiliation: Department of Pathology, University of Athens, Medical School, Greece.
authors.forename: Penelope
authors.initials: P
authors.lastname: Korkolopoulou
mesh_terms: D015415:Biomarkers; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D053208:Kaplan-Meier Estimate; D007943:Leukemia, Hairy Cell / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation; D063868:Patient Outcome Assessment; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3