Hedgehog and m-TOR pathways association with apoptosis resistance and cell cycle deregulation in Chronic Myeloproliferative Diseases

Abstract

Polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) are Chronic Myeloproliferative Neoplasms (NMPC) which are characterized by presenting accumulation of erythrocytes, leukocytes, and morphologically normal platelets and their precursors. Little is known about the cellular and molecular mechanisms involved in the pathophysiology and progression of these disorders, which prevents the description of markers for diagnosis, prognosis and effective therapies. A point mutation in the gene encoding the enzyme Janus Kinase 2 (JAK2 V617F) is present in approximately 90% of patients with PV and 50% of patients with ET and MF, was the main finding of abnormal gene associated with poor prognosis of these diseases. This mutation results in constitutive activation of the enzyme JAK2 and deregulation of cell proliferation and resistance to apoptosis. Our research group described in PV, ET and MF altered expression of genes regulating apoptosis and literature data indicate that deregulation of the cell cycle contributes to the pathophysiology of NMPC. In this project we will investigate the association of Hedgehog signaling pathways and m-TOR with changes to the processes of apoptosis, cell cycle and JAK / STAT in NMPC. The Hedgehog signaling pathway and m-TOR participate in the processes of cell survival and proliferation. The experimental strategy is to evaluate the expression of genes and cell cycle regulatory protein, and apoptotic pathways Hedgehog and m-TOR in leukocytes from patients with NPMC and JAK2 + cell lines treated with inhibitors of JAK2,. To determine the relationship of the Hedgehog pathway and m-TOR to apoptosis and cell cycle in NMPC will be selected genes altered in these diseases for silencing in JAK2 positive strains. The results of this study will contribute to the description of new therapeutic targets independents and dependents of JAK2 kinase activity and for a better understanding of signaling pathways Hedgehog pathway and m-TOR in the pathogenesiso of NMPC.