The NLRP3/EIF2 axis in AML

Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive type of blood cancer. The term leukemia derives from the fact that patients are characterized by high levels of white blood cells (leukocytes) in the blood and bone marrow. This results from uncontrolled proliferation of immature bone marrow precursor cells. The suffix "acute" indicates that patients with this form of leukemia quickly develop symptoms of illness and should be treated immediately. In contrast, there are chronic forms of leukemia with slow disease progression. The pathogenesis of AML derives from aberrant proliferation and accumulation of malignant myeloid progenitor cells. As a result, leukemic cells displace normal bone marrow cells such as red blood cells (erythrocytes), platelets (thrombocytes), and the functional white blood cells (leukocytes) that make up the main part of the immune system. The mechanisms underlying uncontrolled proliferation of AML cells and the inability of the immune system to recognize and eliminate malignant cells, are still not fully understood. Therfore, AML remains a major challenge for patients and their physicians. Younger patients usually receive intensive chemotherapy followed by an allogeneic stem cell transplantation. Due to limited physical fitness elderly or high- risk patients are often not eligible for standard chemotherapy and the prognosis, especially for patients older than 60 years, remains very poor, with a 5-year survival rate of only 10 to 15%. Genetic abnormalities, including chromosomal translocations and gene mutations, have been described as main drivers of AML. In addition, chronic inflammation leads to a particularly strong activity of reactive oxygen and nitrogen molecules, which in turn can also alter or damage DNA. In the present project, the role of the NLRP3 inflammasome in AML is being investigated. The NLRP3 inflammasome is a multiprotein complex that has been closely associated with chronic inflammation. Analyses of bone marrow cells from AML patients show significantly increased expression of NLRP3 compared with healthy controls, suggesting that the NLRP3 inflammasome is likely to play an important role as an inflammation-driving force in AML. Based on our observations, we hypothesize that low NLRP3 expression limits AML cell growth, and, that the Eukaryotic Initiation Factor 2 (eIF2) signaling pathway plays an important role in this process. Therefore, the main goal of this project is to elucidate the relationship between AML, NLRP3 and the eIF2 signaling pathway in order to provide new paths for potential novel therapeutic approaches.