| Project Detail |
The role of lipid droplets in acute myeloid leukaemia
Acute myeloid leukaemia (AML) is high-risk cancer that starts in the differentiation-defective blood-forming cells of the bone marrow (BM). The poor response to treatment is associated with leukaemia – BM stroma interaction. Recent studies identified the cytosolic fat storage organelles, lipid droplets (LDs), as regulators of lipid metabolism and signalling in cells under stress conditions, including chemotherapy. The inhibition of LDs was shown as more effective than the standard-of-care chemotherapy in impairing AML cell proliferation. Funded by the Marie Sklodowska-Curie Actions programme, the ALERT project aims to characterise the LDs in AML and investigate their involvement with the BM stroma in the progression and refractoriness of AML.
Acute Myeloid Leukemia (AML) results from the uncontrolled expansion of differentiation-defective hematopoietic stem/progenitor cells or immature myeloid cells (blasts) in the bone marrow (BM). AML remains a high-risk disease mainly due to treatment refractoriness which is dependent on leukemia-BM stroma interactions. Unfortunately, treatments have only experienced minor developments over the last decades. On the other hand, emerging evidence in cancer metabolism has identified Lipid Droplets (LDs, cytosolic fat storage organelles) as key regulators of lipid metabolism and signalling in cells exposed to stress such as hypoxia, chemotherapy, and nutrient deprivation. However, the precise role of LDs in the pathogenesis and chemoresistance of AML remains poorly investigated. Here, we aim to i) characterize the accumulation and role of LDs in AML, ii) assess the functional impact of blasts- and BM stroma-LDs on AML pathogenesis and chemoresistance, and iii) investigate the involvement of LDs in the progression and refractoriness of AML. Cutting-edge in vitro (AML primary cells, BM-stroma cells) and in vivo assays (patient-derived xenografts) will be used to provide evidence of LDs as a key player in leukemogenesis. Our project is based on solid preliminary single cell-RNA sequencing data indicating that LDs are highly accumulated in AML blasts, and that inhibition of LDs is more effective than the standard-of-care chemotherapy in impairing AML cell proliferation.
Our proposal represents an innovative approach achievable thanks to the complementary knowledge and expertise of two top-notch laboratories in acute leukemia (supervisor) and LDs (collaborator). Results from this study will open new avenues to explore the therapeutic opportunity of LD inhibitors as anti-leukemic co-adjuvant.
This fellowship will enable me to acquire transformational knowledge in leukemia metabolism and will constitute a major first step towards initiating my independent academic career. |
