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Elucidating the role of the tumor suppressor Protein Phoshatase 2A in Chronic Myeloid Leukemia.

Neviani, Paolo (2010) Elucidating the role of the tumor suppressor Protein Phoshatase 2A in Chronic Myeloid Leukemia. PhD Thesis , Università degli Studi di Ferrara.

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    Protein phosphatase-2A (PP2A) is one of the major cellular serine-threonine phosphatases and is involved in the regulation of cell homeostasis through the negative regulation of signaling pathways initiated by protein kinases. As several cancers are characterized by the aberrant activity of oncogenic kinases, it was not surprising that a phosphatase like PP2A has progressively been considered as a potential tumor suppressor. Indeed, multiple solid tumors (e.g. melanomas, colorectal carcinomas, lung and breast cancers) present with genetic and/ or functional inactivation of different PP2A subunits and, therefore, loss of PP2A phosphatase activity towards certain substrates. Likewise, impaired PP2A phosphatase activity has been linked to B-cell chronic lymphocytic leukemia, Philadelphia-chromosome positive acute lymphoblastic leukemia and blast crisis chronic myeloid leukemia (CML). In CML the deregulated tyrosine kinase activity of p210-BCR/ABL oncoproteins is sufficient to induce and sustain the leukemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukemia stem cell is also resistant to imatinib. We have recently reported that the phosphatase activity of PP2A is markedly inhibited in blast crisis and, to a lesser extent, chronic phase CML patient cells and that pharmacologic re-activation of PP2A phosphatase activity by activating drugs such as Forskolin and FTY720 led to growth suppression, enhanced apoptosis impaired clonogenic potential and decreased in vivo leukemogenesis of imatinib-sensitive and -resistant CML-BC and CML-CP patient. Furthermore we have evidence that PP2A inactivation is an event that occurs also at the level of the leukemic stem cell and that PP2A re-activation hampers the survival and self-renewal of CML stem cells and possibly overcome the resistance of CML quiescent stem cells to tyrosine kinase inhibitor monotherapy. Thus, inducing PP2A phosphatase activity has the potential to eradicate CML by efficiently targeting both leukemic stem and progenitor cells regardless of their degree of sensitivity to kinase. Therefore, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for CML patients.

    Item Type:Thesis (PhD Thesis)
    Date:19 March 2010
    Tutor:Volinia, Stefano
    Coordinator:Borea, Andrea
    Institution:Università degli Studi di Ferrara
    Divisions:Dipartimento > Medicina clinica e sperimentale
    Subjects:Area 05 - Scienze biologiche > BIO/17 Istologia
    Uncontrolled Keywords:CML, chronic myeloid Leukemia, PP2A, leucemia mieloide cronica, FTY720, imatinib, onco-soppressore, tumor suppressor
    Deposited on:23 Jul 2010 10:12


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