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Ignatz-Hoover Thesis 11-30.pdf (12.6 MB)

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TLR8 and Nuclear GSK3ß are Novel Therapeutic Targets in AML

Ignatz-Hoover, James J
http://rave.ohiolink.edu/etdc/view?acc_num=case1480509044211523

Abstract Details

2017, Doctor of Philosophy, Case Western Reserve University, Pathology.
Acute myeloid leukemia (AML) is an aggressive disease with a poor 5-year survival of 21% that is characterized by a differentiation arrest of immature myeloid cells. For a rare subtype of AML (Acute promyeloctyic leukemia, 10% of cases) all-trans retinoic acid therapy removes the differentiation block, yielding over a 90% cure rate. However, this treatment is not effective for the other 90% of AML patients, suggesting new differentiation strategies are needed. Using an NBT differentiation screening assay, our lab has defined TLR8 and GSK3ß as novel AML differentiation therapy targets. We show that the TLR7/8 ligand, R848, promotes AML differentiation and growth inhibition in vitro and in vivo in a TLR8/MyD88/p38 dependent manner, exhibiting direct anti-leukemic effects independent of its immunomodulating properties that are currently under investigation in cellular cancer therapies. We show that AML cells exhibit an aberrant nuclear GSK3ß and this nuclear fraction drives AML growth and drug resistance in vivo and in vitro. Nuclear GSK3ß promotes drug resistance partially through activation of the pro-survival NF-¿B signaling pathway. Finally, we show that nuclear GSK3ß localization strongly correlates to poorer patient survival (N=86 HR= 2.2 p=0.006). Nuclear localization of GSK3ß may define a novel oncogenic mechanism as well as a new therapeutic target in AML.
George Dubyak, PhD (Committee Chair)
David Wald, MD PhD (Advisor)
Xiaoxia Li, PhD (Committee Member)
Mark Jackson, PhD (Committee Member)
Parameswaran Ramakrishnan, PhD (Committee Member)
Howard Meyerson, PhD (Committee Member)
124 p.
Cellular Biology; Oncology; Pathology
Acute myeloid leukemia; cancer; GSK3Beta; toll like receptors; differentiation therapy; drug resistance; NF-kappaB

Recommended Citations

Citations

  • Ignatz-Hoover, J. J. (2017). TLR8 and Nuclear GSK3ß are Novel Therapeutic Targets in AML [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1480509044211523

    APA Style (7th edition)

  • Ignatz-Hoover, James. TLR8 and Nuclear GSK3ß are Novel Therapeutic Targets in AML. 2017. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1480509044211523.

    MLA Style (8th edition)

  • Ignatz-Hoover, James. "TLR8 and Nuclear GSK3ß are Novel Therapeutic Targets in AML." Doctoral dissertation, Case Western Reserve University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1480509044211523

    Chicago Manual of Style (17th edition)

case1480509044211523
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© 2016, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.