The NLRP3/EIF2 axis: linking inflammation and tumor progression in acute myeloid leukemia.

Project Details

Description

The NLRP3/EIF2 axes: linking inflammation and tumor progression in acute myeloid leukemia
Research context:
Acute myeloid leukemia (AML) is an aggressive type of blood cancer and the most common cause of leukemia-related mortality. While younger patients are eligible for intensive chemotherapy followed by allogeneic stem cell transplantation, the prognosis for elderly patients (older than 60 years) remains poor, with a 5-year survival rate of approximately 10% to 15%. Thus, there is an urgent need for a better understanding of disease onset and progression in order to develop alternative treatment strategies to improve clinical outcomes.
Hypothesis and innovative aspects:
Chronic inflammation is a hallmark of many types of cancer and is closely related to poor prognosis in cancer patients. Within the innate immune system, inflammation is often driven by inflammasome activation, with the inflammasome component NLRP3 (NOD-, LRR- and pyrin domain-containing protein-3) being one of the best-studied members of the NLR-family. Analyses of bone marrow cells from AML patients shows a significantly increased expression of NLRP3 compared to healthy controls. Furthermore, we observe a strong negative correlation between NLRP3 expression and phosphorylation of eIF2α (eukaryotic Initiation Factor 2α). Since the phosphorylation of eIF2α is a crucial step in promoting cell cycle arrest and apoptosis, we propose the novel idea, that abnormal expression of NLRP3 could prevent apoptosis of AML blast cells by acting on eIF2. This hypothesis was further strengthened by the observation that genetic deletion of NLRP3 not only induces strong eIF2α phosphorylation, but also results in limited proliferation of AML cells. Therefore, the main goal of this project is to elucidate underlying mechanisms leading to increased NLRP3 expression/activation in AML, to study the link between abnormal NLRP3 expression and eIF2α, and to analyse the consequences of NLRP3 inhibition/deletion on the survival of leukemic cells.
Research methods:
Patient AML samples will be provided by our clinical collaboration partner Univ. Prof. Dr. Richard Greil from the Salzburg Cancer Research Institute, Austria. In addition to standard techniques, we will apply CRISPR/cas9 technology (in collaboration with Univ. Prof. Dr. Fritz Aberger, University of Salzburg, Austria), shotgun proteome analysis (in collaboration with Univ. Prof. Dr. Christian Huber, University of Salzburg, Austria) and super-resolution microscopy to unravel the molecular link between NLRP3, eIf2α and blast survival. AML engraftment studies to investigate the role of NLRP3 for cell survival in vivo will be performed in close collaboration with Univ. Prof. Dr. Fritz Aberger (University of Salzburg, Austria).
Researchers involved:
The applicant (PI), a postdoctoral fellow and a PhD student will be mainly responsible for the project. In addition, the team will receive support from computer scientists at FH Hagenberg, Austria, who will contribute to the analyses of public datasets and data generated by proteomic approaches.
Short titleThe NLRP3/EIF2 axis in AML
StatusActive
Effective start/end date1/09/2131/03/25