Understanding the role of stromal cell-derived citrate in acute myeloid leukemia

Details

Supervisors

Van Gastel, Nick

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

Acute myeloid leukemia (AML) is a malignancy of hematopoietic stem and progenitor cells, that develops in the bone marrow. Despite great progress in current treatment schemes, patients invariably relapse after several rounds of chemotherapy. Previous data from the lab show that bone marrow stromal cells (BMSCs) can protect AML cells from chemotherapy in co-cultures, and that BMSCs produce and release citrate. Given its crucial role in metabolism at the intersection of energy generation, biosynthesis and epigenetic regulation, we hypothesized that the BMSC-derived citrate might give AML cells a proliferative advantage or resistance to chemotherapeutic agents. Data from several studies suggest that macrophages, when treated with citrate, have an enhanced cytokine secretion. In particular Interleukin-3 (IL3) and IL6, which have been shown to be essential for AML survival in culture. It has also been reported that citrate accumulation in the cytosol of macrophages may be necessary to provide energy as well as the intermediate metabolites that are crucial for macrophage activation and/or for the inflammatory response. Given that our BMSC cultures are heterogeneous and contain a considerable number of macrophages, this dissertation will therefore explore the effect of citrate on AML cells and macrophages