Anmerkungen:
Tag der Verteidigung: 05.04.2022
Zusammenfassungen in deutscher und englischer Sprache
Beschreibung:
Acute myeloid leukemia (AML) is a heterogeneous, malignant disease which has a high relapse rate and is associated with poor prognosis. The purpose of this dissertation is to analyze/characterize the functional roles of NOX4 in normal hematopoiesis and myeloid malignancies driven by FLT3-ITD mutation and to assess the potential suitability of NOX4 as a therapeutic target. In general, genetic inactivation of Nox4 did not disturb normal hematopoiesis. On the other hand, the assessment of the functional roles of NADPH oxidases (NOXs) in human AML cell lines in vitro showed that NOX4 or p22-phox knockout causes a relatively mild functional impairment, which could only be observed with a sensitive competition assay, and which is most pronounced in FLT3-ITD+ human AML cell lines. Conversely, in the Flt3-ITD-driven myeloproliferative disease (MPD) model, Nox4 deletion further promoted the disease phenotypes at steady-state. Collectively, this study showed for the first time that targeting Nox4 may promote or inhibit AML progression in a context-dependent way. The potential of two novel NOX inhibitors, the proposed NOX1/4 inhibitor setanaxib and the NOX2 inhibitor GSK2795039 was analyzed for the treatment of myeloid malignancies. Setanaxib was very effective to inhibit the growth of myeloid malignant cells especially with long treatment time. Furthermore, the combination of these NOX inhibitors with standard chemotherapy drugs (cytarabin, daunorubicin or midostaurine) revealed strong synergistic effects with respect to growth inhibition of FLT3-ITD+ leukemic cells and a combined effect was visible in vivo. Interestingly, our findings indicated that the growth inhibitory effects of setanaxib as well as the synergism with cytotoxic drugs did not stem from NOX inhibition. Still, setanaxib treatment showed therapeutic potential both in vitro and in vivo. Further investigations are required to test the potential of setanaxib treatment in different pre-clinical leukemia model.