Project Funding Details

Acute myeloid leukemia is a disease of the elderly, current therapies are extremely challenging for the large majority of patients. The metabolic heterogeneity at onset and metabolic clonal evolution, driven by therapy, are essential insights that still remain unclear. In general cancers cells, feature a varied and flexible metabolism depending on nutrient availability, tumor's tissues structural organization and therapeutic selective pressure. HSCs tightly control their metabolism to maintain their survival and their quiescent state. LSCs and HSCs share similar self-renewal and differentiation features, but present many differences. HSCs acquire energy mainly through anaerobic glycolysis, whereas LSCs largely through mitochondrial oxidative respiration. The regulatory mechanism for redox homeostasis differs between LSCs and HSCs. Lipid metabolism is central in LSCs survival. The leading postulate of this proposal is that LSC metabolic necessities represent key targets to overcome therapy resistance in AML. The reliance on OXPHOS may represent a broadly conserved LSC vulnerability. To individuate the metabolic peculiarities of blast and LSCs from that of the healthy HSCs, is critical for the development of new therapies targeting hematological disorders. We aim to study metabolism in normal, and cancer cells with particular aim to leukemic stem cells (LSC). Current risk stratification for AML considers age, performance, WBC, cytogenetic and mutation status. The crucial aims of our research are: i) to determine if the metabolic profile of AML cells at the time of diagnosis can predict the clinical outcome ii) to find early prognostic indicators for developing a new AML risk assessment and iii) to individuate LSC metabolic frailties for new targeted therapies. We will investigate the metabolic landscape of the tumor's bulk and the metabolic dependencies of LSCs for prognostic and therapeutic stratifications of AMLs. Our preliminary data showed a correlation between OXPHOS/PL/SRC levels and outcome in AML patients rising the question of the mechanism determining these metabolic differences. In this context, we have individuated specific high risk AML metabolic profiles to be studied and acted upon including high proton leak, high OXPHOS, MCL1-HK2 interaction and high CD36 expression with high FAO. To reach those aims, that we identified in three working parties, the most up-to-date technologies will be used to characterize leukemic cells' metabolic mechanisms that promote disease progression and therapy resistance. By integrating this knowledge with other specific characteristics, we want to develop innovative risk models for assessing prognosis and facilitating therapeutic decisions, and test innovative strategies to overcome resistance. Findings generated in vitro will be validated in animal models. We are confident that the results obtained might represent a step-forward in understanding the pathobiology of AML and produce tangible improvements in patients' management. Overall results produced by this project will help to describe and validate novel biomarkers of disease progression, and lead to identifying novel actionable targets, in the spirit of personalized medicine LMA are prototype of cancer diseases, their intrinsic evolution recapitulate that of cancer cells. Our study might contribute to generate a thorough understanding of molecular, biochemical and cellular events involved in tumor progression more in general.