The modulation of the hematopoietic system by Paraoxonase-2

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The human enzyme paraoxonase-2 (PON2) counteracts, i.e. hydrolyzes certain bacterial virulence factors and as such is part of the innate immune system. In addition, PON2 is among the critical cellular anti-oxidative enzymes. Its reduction of oxidative stress and impact on subsequent signaling pathways are central to the scope of this project. Due to its function, PON2 is regarded as cyto-protective enzyme and it has been shown to attenuate atherosclerosis in vivo. Studying underlying mechanisms, we previously demonstrated a reduction of mitochondrial and ER stress-induced apoptosis by PON2, resulting in an anti-apoptotic effect that protects cancer cells against cytotoxic effects of chemotherapeutics. In accordance, PON2 is found overexpressed in many tumors and its knock-down induces death of several cancer cells. Alike, many studies associated PON2 with several tumors in patients. Especially in certain leukemias, PON2 levels directly correlate with staging, outcome prognosis and therapy response. With respect to hematopoietic stem cells, this supports the concept that self-renewal and differentiation are centrally regulated by redox-sensitive pathways. Concordantly, we found significant alterations in the hematopoietic compartment of PON2 deficient mice, both at quantitative and functional levels.In stem and progenitor cells, the importance of redox-signaling recently gained considerable interest. However the role of PON2 has never been analyzed. Thus, the goal of this project is to reveal the redox-mediated pathways by which PON2 controls cell cycle regulation, apoptosis, differentiation and function of stem and progenitor cells. This is extended to peripheral blood cells, particularly erythrocytes and stress-induced erythropoiesis. Moreover, we want to identify both PON2 regulating and regulated signaling pathways in cancer and stem cells. Together, our molecular and in vivo studies help to uncover key functions of a potentially pro-oncogenic enzyme clearly relevant to human diseases. This opens new avenues to the Paraoxonase research field and directly links redox-mediated events with hematopoietic stem cell functions.