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Exploiting the MLL-rearranged leukemia gene signature to identify molecular targets for novel therapies

Gracia-Maldonado, Gabriel
http://orcid.org/0000-0001-7336-9720
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573570752309466

Abstract Details

2019, PhD, University of Cincinnati, Medicine: Pathobiology and Molecular Medicine.
Although great advances have been made in the development of therapies for Acute Lymphoid Leukemia (ALL) and Acute Myeloid Leukemia (AML), patients with reciprocal translocations of the 11q23 locus develop acute leukemias (MLL-r leukemias) resistant to conventional chemotherapies. The translocations generates an oncogenic fusion protein comprised of an amino terminus derived from MLL (now called KMT2A) gene fused to a carboxyl terminus derived from one of several different genes. Unfortunately, this disease is highly prevalent in infants accounting for 80% of ALL and 35-50% of AMLs. Novel therapies like small molecules inhibitors and immunotherapies have focused on inhibiting the functions of the MLL-fusion protein (MLL-FP) complex and associated proteins or target proteins that are expressed in a multitude of healthy cells leading to on-target off tumor effects and high toxicities. Therefore, further research is required to understand better the molecular pathobiology of the disease and develop more targeted therapies. Transcriptome studies are one approach to understand the pathobiology and potential vulnerabilities of diseases. MEIS1 and LAMP5 are two genes that have been identified in independent studies as being highly expressed in MLL-r leukemias regardless of age, lineage or fusion partner. MEIS1 have been shown to be required for normal maintenance of Hematopoietic Stem Cells (HSC) by limiting oxidative metabolism and ROS levels in these cells. In MLL-r leukemia, MEIS1 is essential for the maintenance of MLL-FP induced transformation. Furthermore, MEIS1 is required for the propagation of MLL-r leukemias in vivo. Similar to healthy HSC, MEIS1 regulate the hypoxic state through blocking of the induction of oxidative phosphorylation and generation of ROS, a mechanism required to retain stem cell properties in MLL-r leukemias. MEIS1 control this effects partly by regulating the expression of the Hepatic Leukemia Factor (HLF). MLL-r leukemias are greatly affected by induction of oxidative phosphorylation using a pyruvate dehydrogenase kinase (PDK) inhibitor, as compared to normal HSC. Thus, activation of oxidative phosphorylation is a significant vulnerability of MLL-r leukemias which should be exploited for therapeutic purposes. The Lysosomal Associated Membrane Protein 5 is a much less studied gene compared to MEIS1. LAMP5 is mainly expressed in the brain and in plasmacytoid Dendritic Cells (pDCs) in humans. Loss of Lamp5 in mice only leads to a mild behavioral phenotype. In human pDCs, LAMP5 function as an innate immune signaling switch, regulating the localization of TLR9 between early endosome and lysosomes, and the signaling between Type-1 Interferon (IFN-1) and Pro-inflammatory (NF?B) signaling. In MLL-r leukemias, LAMP5 expression is directly controlled by the MLL-FP and is essential for the survival of MLL-r leukemias in vitro and in vivo. In contrast to unactivated pDCs, LAMP5 is localized in in the lysosome of MLL-r leukemias and is required for the activation of TLRs. Downregulation of LAMP5 leads to decrease activation of NF?B and increased activation of IRF7 and IFN-1 signaling. MLL-r leukemias are sensitive to detection and targeting of LAMP5 in the surface of the cells. In summary, our findings provide two novel molecular mechanism for potential therapeutic targeting of MLL-r leukemia.
Ashish Kumar, M.D. Ph.D. (Committee Chair)
Jose Cancelas-Perez, M.D. (Committee Member)
Gang Huang, Ph.D. (Committee Member)
James Mulloy, Ph.D. (Committee Member)
Daniel Starczynowski, Ph.D. (Committee Member)
171 p.
Molecular Biology
Gene expression; MEIS1; Innate Immune Signaling; MLL leukemia; LAMP5; Oxidative Phosphorylation

Recommended Citations

Citations

  • Gracia-Maldonado, G. (2019). Exploiting the MLL-rearranged leukemia gene signature to identify molecular targets for novel therapies [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573570752309466

    APA Style (7th edition)

  • Gracia-Maldonado, Gabriel. Exploiting the MLL-rearranged leukemia gene signature to identify molecular targets for novel therapies. 2019. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573570752309466.

    MLA Style (8th edition)

  • Gracia-Maldonado, Gabriel. "Exploiting the MLL-rearranged leukemia gene signature to identify molecular targets for novel therapies." Doctoral dissertation, University of Cincinnati, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573570752309466

    Chicago Manual of Style (17th edition)

ucin1573570752309466
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© 2019, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.