Studio dell'interazione tra i pathway di AKT e Notch1 nel modello di Leucemia linfoblastica acuta a cellule T MOLT4

In this work we studied the PI3K-Akt pathway and its interaction with Notch1 in the T-ALL cell line MOLT-4. Akt is a serine-threonine kinase which acts downstream to PI3K to regulate many biological processes, such as proliferation, apoptosis and growth. Akt constitutive activation has been implicated in both the pathogenesis and the progression of a wide variety of neoplasias. Notch1 is a transmembrane receptor that mediates intracellular signaling involved in cell differentiation and cell survival. Somatic activating mutations in Notch1 have been found in more than 50% of human T-ALL samples. Our results showed that in MOLT-4 cell line the PI3K-Akt pathway is constitutively activated. Indeed MOLT-4 cells did not express the tumor suppressor gene PTEN which is a negative modulator of the PI3K-Akt pathway. Specific blockade of the PI3K-Akt pathway with the inhibitor LY294002 resulted in an increase of apoptosis and in the activation of glycogen synthase kinase-3beta (Gsk-3b). The apoptotic effect of LY294002 was partially reversed through administration of Lithium Chloride, which inhibits Gsk-3b activity. Blockade of the PI3K-Akt pathway resulted in a decrease of Notch1 protein levels. The downstream targets of Notch1 pathway, preTCRa and Hes1, were also found to be down regulated. We demonstrated that inhibition of the PI3K-Akt pathway enhanced Notch1 specific phosphorylation in