The chronic myeloproliferative neoplasms (MPNs), are characterized by a Janus 
Kinase (JAK)-2 V617F point mutation but this molecular abnormality does not 
explain by itself the pathogenesis of these disorders, or the phenotypic 
diversity associated with essential thrombocythemia, polycythemia vera (PV), and 
myelofibrosis. Beyond the JAK/signal transducer and activator of transcription 
network, a wide number of molecular alterations were described in MPN including 
the fosfatidilinositolo-3-chinasi (PI3K)/protein kinase B (Akt)/mammalian target 
of rapamycin (mTOR) pathway constitutive activation. Several pathway inhibitors 
were developed, including everolimus, up to the latest class of catalytic 
inhibitors such as BKM120 and BEZ235. In this review, we present some clinical 
and experimental evidence showing that the PI3K/Akt/mTOR pathway could represent 
a therapeutic target in MPNs. In in vitro studies, everolimus has been shown to 
inhibit cell proliferation and clonogenic potential in human and murine JAK2 
V617F mutated cell lines. Patients with PV and primary myelofibrosis 
hematopoietic progenitors were significantly more sensitive to everolimus 
compared with healthy control subjects. Of much interest, a combination of 
everolimus and the JAK1/2 inhibitor, ruxolitinib, showed strong synergism in 
inducing cell cycle arrest and blockade of cell proliferation. Similar data were 
obtained using a dual PI3K/mTOR inhibitor, BEZ235, with activity that was also 
shown in preclinical murine models. A multicenter phase I/II trial with 
everolimus in myelofibrosis documented a well tolerated clinical efficiency in 
terms of spleen size reduction and resolution of systemic symptoms and pruritus. 
These observations indicate that the PI3K/Akt/mTOR pathway might represent a 
novel target for treatment in MPN. The synergism demonstrated in vitro with JAK2 
inhibitors could open additional therapeutic possibilities based on concurrent 
targeting of different pathways that might optimize efficacy and reduce toxicity 
in patients.