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The role of THPO/MPL signaling in AML1-ETO self-renewal

Griesinger, Andrea

Abstract Details

2011, MS, University of Cincinnati, Medicine: Cell and Molecular Biology.

Chromosomal translocation (8;21)(q22;q22) gives rise to the fusion gene AML1-ETO (AE) which is present in 10-15% of all acute myeloid leukemia and 40% of the French-American-British M2 type AML. Though AE is not sufficient to cause transformation, it does promote self-renewal of hematopoietic stem (HSC) and progenitor cells as well as block lineage differentiation. In an AE cell model, our lab has previously shown that AE expression was associated with increased DNA damage and high levels of p53, suggesting AE might also somehow promote a survival mechanism to counter these negative effects. We have shown AE up regulates expression of Bcl-xL through Thrombopoietin (THPO)/MPL signaling pathway and signaling through this pathway was required for AE survival and self-renewal. We found Bcl-xL promoted survival of human CD34 positive cells independently of its classical BH3 interactions, and this was specific to Bcl-xL. In this study, we show that the more mature CD34 negative cells utilize the classical functions of Bcl-xL in which BH3 interactions are required, demonstrating the cell type specific functions of Bcl-xL even in the context of a human cell expressing the AE oncogene. We were also interested in knowing how much of AE function could be explained by the increase in THPO/MPL signaling. We show that expression of MPL in normal cord blood cells was not sufficient to recapitulate AE long-term culture. Increased expression of MPL does partially promote a self-renewal phenotype but is insufficient to suppress differentiation. This suggests THPO/MPL signaling cooperates with other AE functions to promote self-renewal. Since THPO/MPL signaling has been shown to have roles in both survival and self-renewal programming in AE self-renewal, it could be a potential therapeutic target in t(8;21) positive AML .

James Mulloy, PhD (Committee Chair)
Robert Brackenbury, PhD (Committee Member)
Daniel Starczynowski, PhD (Committee Member)
Susanne Wells, PhD (Committee Member)
16 p.

Recommended Citations

Citations

  • Griesinger, A. (2011). The role of THPO/MPL signaling in AML1-ETO self-renewal [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1321969049

    APA Style (7th edition)

  • Griesinger, Andrea. The role of THPO/MPL signaling in AML1-ETO self-renewal. 2011. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1321969049.

    MLA Style (8th edition)

  • Griesinger, Andrea. "The role of THPO/MPL signaling in AML1-ETO self-renewal." Master's thesis, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1321969049

    Chicago Manual of Style (17th edition)