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

• Published in: Scientific reports Vol. 6; no. 1; p. 21252
• Main Authors: 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, Piperi, Christina, Korkolopoulou, Penelope
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 19.02.2016
• Subjects: AKT protein; Biomarkers; Caspase; Caspase 3 - genetics; Caspase 3 - metabolism; Caspase-3; Cell proliferation; DNA Mutational Analysis; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression; Hairy cells; Kaplan-Meier Estimate; Leukemia; Leukemia, Hairy Cell - genetics; Leukemia, Hairy Cell - metabolism; Leukemia, Hairy Cell - mortality; Leukemia, Hairy Cell - pathology; Medicin och hälsovetenskap; Metabolic pathways; Microvasculature; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Multivariate analysis; Mutation; Patient Outcome Assessment; Proportional Hazards Models; Proteins; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Raf protein; Rapamycin; Signal Transduction; TOR protein; TOR Serine-Threonine Kinases - metabolism
• ISSN: 2045-2322; 2045-2322
• 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.