Περίληψη:
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.
Συγγραφείς:
Lakiotaki, E.
Levidou, G.
Angelopoulou, M.K.
Adamopoulos, C.
Pangalis, G.
Rassidakis, G.
Vassilakopoulos, T.
Gainaru, G.
Flevari, P.
Sachanas, S.
Saetta, A.A.
Sepsa, A.
Moschogiannis, M.
Kalpadakis, C.
Tsesmetzis, N.
Milionis, V.
Chatziandreou, I.
Thymara, I.
Panayiotidis, P.
Dimopoulou, M.
Plata, E.
Konstantopoulos, K.
Patsouris, E.
Piperi, C.
Korkolopoulou, P.
Λέξεις-κλειδιά:
B Raf kinase; biological marker; caspase 3; mitogen activated protein kinase; mitogen activated protein kinase 1; mitogen activated protein kinase 3; protein kinase B; target of rapamycin kinase, dna mutational analysis; gene expression; genetics; hairy cell leukemia; Kaplan Meier method; metabolism; mortality; mutation; outcome assessment; pathology; proportional hazards model; signal transduction, Biomarkers; Caspase 3; DNA Mutational Analysis; Extracellular Signal-Regulated MAP Kinases; Gene Expression; Kaplan-Meier Estimate; Leukemia, Hairy Cell; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mutation; Patient Outcome Assessment; Proportional Hazards Models; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases
