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

作者：Lakiotaki Eleftheria^*; Levidou Georgia; Angelopoulou Maria K; Adamopoulos Christos; Pangalis Gerassimos; Rassidakis George; Vassilakopoulos Theodoros; Gainaru Gabriella; Flevari Pagona; Sachanas Sotirios; Saetta Angelica A; Sepsa Athanasia; Moschogiannis Maria; Kalpadakis Christina; Tsesmetzis Nikolaos; Milionis Vassilios; Chatziandreou Ilenia; Thymara Irene; Panayiotidis Panayiotis; Dimopoulou Maria; Plata Eleni; Konstantopoulos Konstantinos; Patsouris Efstratios

来源：Scientific Reports, 2016, 6(1): 21252.

DOI：10.1038/srep21252

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.

• 出版日期2016-2-19