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Circular peptide therapeutics for Acute Myeloid Leukemia
Zuzanna Edyta Kieron
Karoline Kollmann
Dagmar Stoiber-Sakaguchi
Master thesis - University of Veterinary Medicine Vienna - 2023
Acute myeloid leukemia (AML) is characterized by an aggressive clinical course and a high mortality rate. It is driven by leukemic stem cells with a highly heterogeneous mutational background, resulting in different subtypes. The properties of leukemic stem cells (e.g., epigenetic pattern, signaling) differ from those of the mass AML population, making these cells difficult to eliminate. The standard of care for patients has changed only minimally over the past four decades, and there is an urgent need to develop patient-specific treatment options. Previous studies and preliminary data suggest that plant-derived circular peptides may be novel treatment options for AML. We use a mouse model of hematopoietic progenitor cells (HPCLSK) to mimic AML subtypes. These cells can repopulate the entire hematopoietic cell pool and induce disease in vivo after transformation. In the study two different AML oncogenes (RUNX1-RUNX1T1 and KMT2A-MLLT3) were used to elute the efficacy of the natural cyclotide Caripe 11 and 8 as well as the synthetic prototype cyclotide T20K for AML. The effects on cell viability were analyzed using flow cytometry based viability assays. The underlying mechanisms of the tested cyclotides were investigated by analyses of proliferation, apoptosis, and myeloid differentiation. The level of apoptosis-related proteins was determined after T20K treatment by using Western Blots. We determined the IC50 values of Caripe (1.3 - 2.4μM) and T20K (5-10 μM) for biological replicates of RUNX1-RUNX1T1+ and KMT2A-MLLT3+ cell lines. The results of cell viability assays revealed that the cyclotides lowered the cell viability of distinct biological replicates to a different degree. Caripe treatment of murine AML cells induced apoptosis and T20K treatment induced apoptosis and necrosis. Moreover, Caripe treatment did not induce myeloid differentiation. T20K treatment altered the levels of apoptosis-related proteins. RUNX1-RUNX1T1+ cells increased levels of Bcl-xl and p53 and lowered levels of ATM upon T20K treatment. The tested cyclotides show a promising natural product-based treatment option for AML subtypes. Our preliminary results open a novel research area investigating in depth the mechanisms underlying cyclotide treatment and possible novel combinatorial treatment strategies.
Masterarbeit - Veterinärmedizinische Universität Wien - 2023
Englisch
2023
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