<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Classification of acute myeloid leukemia as\r\na ferroptosis-sensitive malignancy suggesting the\r\ndevelopment of arsenic trioxide mediated\r\nferroptosis-inducing combination therapies"^^ . "Despite advancements in the treatment of acute myeloid leukemia (AML), the 5-year survival\r\nrate of AML patients remains poor. The majority of patients face disease recurrence partly due\r\nto acquired resistance against classical cell death programs. Therefore, exploiting alternative\r\nforms of cell death, such as ferroptosis, may allow to design novel therapies to limit survival or\r\noccurrence of such resistant AML clones.\r\nFerroptosis is a recently identified iron-dependent and non-apoptotic form of cell death. It is\r\ncharacterized by an excessive ROS-induced peroxidation of poly-unsaturated fatty acids\r\n(PUFAs) within cell membranes and its chemical induction has shown promising therapeutic\r\npotential in multiple solid cancer entities. The work provided here aimed to investigate the role\r\nof ferroptosis in AML and explore its therapeutic possibilities for the treatment of AML.\r\nIn this thesis, I first investigated the overall dependency of AML on ferroptosis-related genes\r\n(FRGs) using publicly available data sets. Secondly, I evaluated the ferroptosis sensitivity of\r\nvarious AML cell lines through chemical inhibition and genetic deletion of ferroptosis\r\nregulators. With these insights, I demonstrated the essentiality of the master ferroptosis\r\nsuppressor GPX4 in AML cell lines in vitro as well as in vivo and revealed high sensitivity of\r\nAML cell lines to chemical ferroptosis induction with Imidazole Ketone Erastin (IKE). In\r\naddition, I described the prognostic value of several FRGs and generated a 7-gene ferroptosis\r\nsignature as a powerful predictor of patient survival.\r\nBy performing a comprehensive drug screen aimed at assessing the ferroptosis-inducing\r\ncapacity of the drugs, I identified arsenic trioxide (ATO) as a potent inducer of ferroptosis in\r\nAML cells. Notably, the detailed characterization of the drug’s mechanism of action on the\r\nRNA level using SLAM-Sequencing revealed the activity of the iron-metabolism gene HMOX1\r\nas being essential for ATO-induced ferroptosis. Mechanistically, we showed that ATO directly\r\ninteracts with GPX4, one of the major ferroptosis-suppressive regulators, resulting in its\r\ninhibition and degradation by the proteasomal system. These findings position ATO as a new\r\nclass II ferroptosis-inducing agent directly acting on GPX4, for which no clinically usable\r\ninhibitor exists to date.\r\nBy performing targeted mass spectrometry and metabolite tracing experiments, we highlighted\r\nthe importance of glutaminolysis for glutathione (GSH) synthesis. I further demonstrated that\r\nATO treatment results in upregulation of metabolic pathways providing cysteine for GSH\r\nsynthesis; namely SLC7A11-mediated cystine-uptake and the transsulfuration pathway.\r\nChemical inhibition as well as genetic deletion of these pathways combined with ATO\r\ntreatment showed strong synergistic effects marking these pathways as new targetable\r\nvulnerabilities in AML to enhance ATO-induced ferroptosis.\r\nBy combining these findings, I designed a novel triple combination therapy (ATO+\r\nCB-839+PPG) targeting the glutaminolysis and transsulfuration pathways in combination with\r\nATO-mediated GPX4 inhibition and degradation. I demonstrated that the triple combination\r\ntherapy resulted in high efficacy in killing AML cell lines as well as primary AML patient\r\nsamples at diagnosis and relapse. Moreover, this triple combination therapy was effective in\r\nvenetoclax + azacytidine (VenAza) resistant AML cell lines, providing a potential means to\r\novercome VenAza resistance.\r\nMoreover, I demonstrated that the ferroptosis inducers ATO and IKE synergize with VenAza\r\ntreatment, offering additional promising combination therapies.\r\nIn summary, the results in this thesis classify AML as one of the most ferroptosis-sensitive\r\ncancer entities. Moreover, we revealed the ferroptosis-inducing capacity of ATO as a novel\r\nGPX4 inhibitor and degrader. Detailed characterization of the drug’s mechanism on the genetic\r\nand metabolic level enabled me to design new effective combination therapies exploiting newly\r\nidentified vulnerabilities in AML. These results provide a rational basis for a pre-clinical and\r\nsubsequent clinical evaluation of ferroptosis-inducing therapies in AML patients."^^ . "2024" . . . . . . . "Andreas"^^ . "Narr"^^ . "Andreas Narr"^^ . . . . . . "Classification of acute myeloid leukemia as\r\na ferroptosis-sensitive malignancy suggesting the\r\ndevelopment of arsenic trioxide mediated\r\nferroptosis-inducing combination therapies (PDF)"^^ . . . "Thesis_AndreasNarr_final.pdf"^^ . . . "Classification of acute myeloid leukemia as\r\na ferroptosis-sensitive malignancy suggesting the\r\ndevelopment of arsenic trioxide mediated\r\nferroptosis-inducing combination therapies (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Classification of acute myeloid leukemia as\r\na ferroptosis-sensitive malignancy suggesting the\r\ndevelopment of arsenic trioxide mediated\r\nferroptosis-inducing combination therapies (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Classification of acute myeloid leukemia as\r\na ferroptosis-sensitive malignancy suggesting the\r\ndevelopment of arsenic trioxide mediated\r\nferroptosis-inducing combination therapies (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Classification of acute myeloid leukemia as\r\na ferroptosis-sensitive malignancy suggesting the\r\ndevelopment of arsenic trioxide mediated\r\nferroptosis-inducing combination therapies (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Classification of acute myeloid leukemia as\r\na ferroptosis-sensitive malignancy suggesting the\r\ndevelopment of arsenic trioxide mediated\r\nferroptosis-inducing combination therapies (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #33929 \n\nClassification of acute myeloid leukemia as \na ferroptosis-sensitive malignancy suggesting the \ndevelopment of arsenic trioxide mediated \nferroptosis-inducing combination therapies\n\n" . "text/html" . .