Year: 2020
Type: dissertation
Abstract: Acute Myeloid Leukemia (AML) is a heterogeneous disease that is associated with a remarkably diverse group of genetic mutations that contribute to its biological complexity directly, or indirectly by triggering downstream cellular reactions. Given these complexities, identification of a single therapeutic strategy that can be effective against a wide range of AML subgroups remains challenging and very few effective novel antileukemic agents have been developed in the past 30 years. Consequently, the overall outcome of patients with AML remains poor. Despite aggressive chemotherapies, AML patients may not achieve remission even after two courses of induction (primary non-responders). Here, our retrospective data indicate that in primary non-responders with AML, remissions following a third induction course are uncommon and short-lived if not consolidated by stem cell transplant (SCT) . Thus, our data indicates that a 3rd induction should only be offered to primary non-responders with AML if an SCT strategy is in place. Collectively, this background highlights an urgent need for development of novel antileukemic strategies. ClpP is a mitochondrial protease that is overexpressed in leukemic cells from approximately half of patients with AML. It degrades damaged or misfolded proteins inside mitochondria and has a central role in maintaining the integrity of mitochondrial metabolism by functioning as a protein quality control mediator. Herein, through genetic and chemical investigations, we demonstrate that ClpP activation results in prominent anti-leukemia and anti-lymphoma effects. We identified a new class of antineoplastic compounds -imipridones- as potent ClpP activators. ClpP activation induces cell death in leukemia and lymphoma cells and stem cells and exerts antitumor effects in vivo whereas normal hematopoietic cells display resistance. In primary AML samples, sensitivity to ClpP activators correlates with pre-treatment ClpP expression level. Mechanistically, binding of imipridones to ClpP enhances proteolysis by enlarging the axial pores of the enzyme. ClpP activation impairs oxidative phosphorylation through reductions in respiratory chain complex subunits and abrogates mitochondrial morphology and function. The currently most potent ClpP activators, imipridones, are being evaluated in clinical trials. Our approach provides groundwork for further development of ClpP activators and represents a first-in-class therapeutic strategy for a subset of hematologic malignancies.
Source: TSpace (University of Toronto)
Author: Sarah F. Zarabi
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Leukemia and Lymphoma Society, Canadian Light Source, Canada Research Chairs, National Institutes of Health, University of Texas MD Anderson Cancer Center, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Western Economic Diversification Canada, National Research Council Canada, Ontario Ministry of Research and Innovation, National Cancer Institute
OpenAlex ID: W3155657040