Potential role of AKT/mTOR signalling proteins in hairy cell leukaemia: Association with BRAF/ERK activation and clinical outcome

Eleftheria Lakiotaki, Georgia Levidou, Maria K. Angelopoulou, Christos Adamopoulos, Gerassimos Pangalis, George Rassidakis, Theodoros Vassilakopoulos, Gabriella Gainaru, Pagona Flevari, Sotirios Sachanas, Angelica A. Saetta, Athanasia Sepsa, Maria Moschogiannis, Christina Kalpadakis, Nikolaos Tsesmetzis, Vassilios Milionis, Ilenia Chatziandreou, Irene Thymara, Panayiotis Panayiotidis, Maria DimopoulouEleni Plata, Konstantinos Konstantopoulos, Efstratios Patsouris, Christina Piperi, Penelope Korkolopoulou

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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.

Original languageEnglish
Article number21252
JournalScientific Reports
StatePublished - 19 Feb 2016
Externally publishedYes


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