A. mTORC1 gene expression and involvement in Myeloproliferative Neoplasms

The myeloproliferative neoplasms (MNPs) are characterized by accumulation of erythrocytes, leukocytes and platelets morphologically normal and their precursors. In recent years several studies have sought to understand the cellular and molecular mechanisms involved in the pathophysiology and progression of these disorders in order to find diagnostic and prognostic markers and effective therapies. The point mutation in the gene encoding the enzyme Janus kinase 2 (JAK2 V617F), present in approximately 90% of PV patients and in 50% of patients with ET and MF was the main abnormal genetic finding associated with these diseases. This mutation results in constitutive activation of JAK2 enzyme and the deregulation of cell proliferation and resistance to apoptosis. Our research group described in PV, ET and MF altered expression of apoptosis regulatory genes and literature data suggest that deregulation of the cell cycle contributes to the pathophysiology of MNPs. In this project the aim was to investigate the signaling pathway of the association m-TOR with the changes of the cell cycle and JAK / STAT in NMPs. The signaling pathway participates in the m-TOR cell survival and proliferation processes. The experimental strategy was to evaluate the expression of genes and proteins, regulators of m-TOR pathway in leukocytes from patients with and NPMC cell lines treated with the JAK2 JAK2 + and AKT inhibitors. To determine the relationship of m-TOR pathway with MNPs has been selected the eIF4E gene deregulated in these disorders to observe their modulation in pharmacologically inhibited cells lines JAK 2 positive. Results of this study contribute to the description of new therapeutic targets of dependent and independent JAK2 kinase activity and to a better understanding of the signaling pathway of participation m-TOR in the pathophysiology of NMPs. (AU)