Experimental modulation of metabolic plasticity in acute myeloid leukemia as a new therapeutic approach

Acute Myeloid Leukemias (AMLs) are hematologic malignancies characterized by an infiltration of clonal and abnormally differentiated cell of the hematopoietic system the bone marrow, blood, and other tissues. Despite the achievements of the health care system with longer life expectation and better health condition in the elderly, traditional chemotherapy and even new less toxic therapies, as Azacytidine Venetoclax combination, still are extremely challenging for the large majority of AML patients. Success rate too is still far from optimal. A different approach for AML patients care is much needed. On this purpose, we have explored the molecular alterations leading to AML metabolic plasticity and the efficacy of a therapeutic strategy aimed to impinge energy demand in AML primary blasts and cell line models. The evolution of the metabolic alterations in AML have been addressed using indirect molecular investigations and metabolic bioenergetics assessments. In this work, we have highlighted the role of mitochondrial and glycolytic metabolism that occurred in AML cells focusing our attention on principal fuel usage to AML cells energy demand. By comparing mitochondrial respiration of normal human hematopoietic progenitors (HPCs) to that of primary blasts obtained from AML patients we saw that AML blast cells present lower spare respiratory capacity than HPCs, indicating their vulnerability to oxidative stress. AMLs cells deep analysis of principal fuel substrate usage shows a dependency on fatty acids (FA) but also a great flexibility, since the cells can switch to glucose or glutamine to meet their energetic needs. Our results indicate that AML can be targeted by metabolic oriented drugs, but is necessary to target simultaneously different metabolic pathways. Ascorbate (inhibition of glycolysis) and Buformin (shut off complex I) combined treatment in AML decrease the energy demand. This correlates with the incapacity of AML blasts to compensate the requirement in total ATP production rate, and with the increased percentage of apoptotic cells, especially in leukemia cells carrying the NPM1 gene mutation (type A) and the DNMT3A R882C mutation. This investigation sheds light on metabolic switch that occurred in AML, and possible metabolic escapes to pharmacological approach. To this regard our attention has been focused on the identification of metabolic signature of AML to evaluate new therapeutic options. Buformin and Ascorbate combined pharmacological intervention, aimed to arrest energy consumption in AML cells, and effectively inhibiting transplantable leukemic cells growth with low toxicity on normal bone marrow stem cells, indicates that metabolic inhibition is a promising alternative strategy to the high cytotoxicity of traditional chemotherapy treatments.