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Novel therapies for treatment of Ph+ acute leukemias

Walker, Christopher James
http://rave.ohiolink.edu/etdc/view?acc_num=osu1374148492

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Chronic myelogenous leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) are driven by the highly active BCR-ABL1 oncogenic kinase. Current treatments include the use of Abl tyrosine kinase inhibitors (TKIs) (e.g. imatinib, dasatinib, nilotinib), and have significantly improved prognoses compared to previous therapies. However, some CML patients do not respond or become refractory to TKIs, and half of Ph+ ALL patients do not survive 3 years after diagnosis. Therefore, new treatments are needed, and advancing the knowledge of molecular mechanisms governing blastic transformation, and leukemic cell survival, proliferation and self-renewal will offer new targets for designed therapies. Many of the pathways by which BCR-ABL1 perpetuates leukemogenesis involve increases in the expression and shuttling activity of RNA binding proteins that transport their cargoes between the nucleus and cytoplasm. However, proteins larger than about 40kDa require the assistance of karyopherins to pass through the nuclear pore complex between the nucleus and cytoplasm. The karyopherin Exportin-1 (XPO1) has been implicated in several hematologic and solid tumor cancers, and has been shown to directly export proteins regulating survival, self-renewal and proliferation including: SET, p53, p21, FOXO, and RB. In the work summarized herein we describe that XPO1 is upregulated in CML and Ph+ ALL blasts when compared to healthy progenitor cells, and that treatment of leukemic cells with a specific XPO1 inhibitor results in altered trafficking of proteins dysregulated by BCR-ABL1. Moreover, pharmacologic inhibition of XPO1 selectively killed leukemic cells in vitro, with little toxicity to healthy donor progenitor cells and significantly increased the survival of treated animals in a terminal stage (blast crisis, BC) CML mouse model. This compound is currently in two Phase I clinical trials and the reported results of administration to an accelerated phase CML patient indicate it can successfully reduce leukemic burden. One of the specific shuttling proteins affected by XPO1 inhibition is heterologous ribonucleotide binding protein (hnRNP) A1, which functions to export SET mRNA, an inhibitor of protein phosphatase 2A (PP2A). This leads to increased SET protein levels and decreased PP2A activity. Notably, PP2A inactivation has been observed in other malignancies, and high expression of endogenous PP2A inhibitors is a poor prognostic factor. In fact, our previous work demonstrated that pharmacologic activation of PP2A by treatment with FTY720 (also called Fingolimod and Gilenya) is sufficient to kill leukemic stem/progenitor cells. However, FTY720 possesses undesired immunosuppressive activity, through its phosphorylation by endogenous kinases and subsequent activation of the sphingosine-1-phosphate receptor 1 (S1PR1) pathway. Conversely, the anti-leukemic activity of FTY720 is not dependent on its phosphorylation, and thus we have uncoupled these two activities by designing compounds related to FTY720 that are unable to be phosphorylated. This work describes data showing these compounds display equally potent anti-leukemic activities when compare to FTY720, but do not activate the S1PR1 pathway, and are non-immunosuppressive when used in vivo. Thus, through direct pharmacologic activation of PP2A, or by targeting the upstream shuttling protein XPO1, we have discovered two promising new therapeutic strategies for eradication of BCR-ABL1+ leukemic cells.
Danilo Perrotti, MD PhD (Advisor)
Michael Caligiuri, MD (Committee Member)
Guido Marcucci, MD (Committee Member)
Don Benson, MD PhD (Committee Member)
130 p.
Molecular Biology
CML; Leukemia; KPT-330; Exportin-1; BCR-ABL1; PP2A

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Citations

  • Walker, C. J. (2013). Novel therapies for treatment of Ph+ acute leukemias [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1374148492

    APA Style (7th edition)

  • Walker, Christopher. Novel therapies for treatment of Ph+ acute leukemias. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1374148492.

    MLA Style (8th edition)

  • Walker, Christopher. "Novel therapies for treatment of Ph+ acute leukemias." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1374148492

    Chicago Manual of Style (17th edition)

osu1374148492
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© 2013, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.