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  • 1. Gracia-Maldonado, Gabriel Exploiting the MLL-rearranged leukemia gene signature to identify molecular targets for novel therapies

    PhD, University of Cincinnati, 2019, 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 affecte (open full item for complete abstract)

    Committee: 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) Subjects: Molecular Biology
  • 2. Melgar, Katelyn A polypharmacologic strategy for overcoming adaptive therapy resistance in AML by targeting immune stress response pathways

    PhD, University of Cincinnati, 2019, Medicine: Immunology

    Targeted inhibitors to oncogenic kinases demonstrate encouraging clinical responses early in the treatment course, however most patients will relapse due to target-dependent mechanisms that mitigate enzyme-inhibitor binding, or through target-independent mechanisms, such as alternate activation of survival and proliferation pathways, known as adaptive resistance. Here we describe mechanisms of adaptive resistance in FLT3 mutant acute myeloid leukemia (AML) by examining integrative in-cell kinase and gene regulatory network responses after oncogenic signaling blockade by FLT3 inhibitors (FLT3i). We identified activation of innate immune stress response pathways after treatment of FLT3-mutant AML cells with FLT3i and showed that innate immune pathway activation via the IRAK1/4 kinase complex contributes to adaptive resistance in FLT3-mutant AML cells. To overcome this acute adaptive resistance mechanism, we developed a small molecule that simultaneously inhibits FLT3 and IRAK1/4 kinases. The multi-kinase FLT3-IRAK1/4 inhibitor eliminated adaptively resistant FLT3-ITD AML cells in vitro and in vivo, and displayed superior efficacy as compared to current targeted FLT3 therapies. These findings uncover a polypharmacologic strategy for overcoming adaptive resistance to therapy in AML by targeting immune stress response pathways.

    Committee: Daniel Starczynowski Ph.D. (Committee Chair); H. Leighton Grimes Ph.D. (Committee Member); Ashish Kumar M.D. (Committee Member); Chandrashekhar Pasare (Committee Member); William Seibel Ph.D. (Committee Member) Subjects: Oncology
  • 3. Smith, Molly Alternative Splicing and Regulation of Innate Immune Mediators in Normal and Malignant Hematopoiesis

    PhD, University of Cincinnati, 2019, Medicine: Cancer and Cell Biology

    The innate immune system is a complex network that recognizes and responds to foreign particles. Innate immune signaling is fundamentally involved in inflammation and increasing evidence implicates chronic innate and inflammatory signaling as a risk factor in cancer and hematologic malignancies. Recent studies have implicated the dysregulation of innate immune signaling in the pathogenesis of Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). However, the precise genetic alterations that cause innate immune signaling activation in hematologic malignancies are not fully defined. Hematologic malignancies have a particularly high frequency of mutations in RNA splicing factors. How these mutations contribute to disease is not fully understood. A global analysis of exon usage in AML samples revealed a subset of genes is regulated exclusively at the isoform level in leukemia, resulting in anticorrelated expression of individual RNA isoforms. Many of these genes regulated by RNA isoform changes are associated with inflammatory and immune pathways. IRAK4 was the most significant immune pathway gene that undergoes isoform switching. Increased expression of the long isoform of IRAK4 (IRAK4-L), which includes exon 4, was found in MDS and AML cell lines and primary patient samples and results in maximal activation of NF-kB. Elevated IRAK4-L isoform expression is associated with poor prognosis in MDS and AML and is significantly associated with mutations in splicing factor U2AF1. Further, U2AF1 directly regulates the splicing of IRAK4 to increase the expression of IRAK4-L. Inhibition of IRAK4 abrogates leukemic growth in vitro and in vivo and is more efficacious in AML cells with U2AF1 mutations and/or higher expression of the IRAK4-L isoform. Thus, mutations in U2AF1 splicing factor induce expression of therapeutically targetable "active" IRAK4 isoforms and provide the first genetic link to activation of chronic innate immune signaling in MDS and AML. The conseq (open full item for complete abstract)

    Committee: Daniel Starczynowski Ph.D. (Committee Chair); Jose Cancelas-Perez M.D. (Committee Member); Matthew Flick Ph.D. (Committee Member); Kakajan Komurov Ph.D. (Committee Member); Nathan Salomonis M.D. (Committee Member) Subjects: Oncology