The Role of Metabolism in the Development of Personalized Therapies in Acute Myeloid Leukemia

Abstract

Despite significant recent advances in our understanding of the biology and genetics of acute myeloid leukemia (AML), current AML therapies are mostly based on a backbone of standard chemotherapy which has remained mostly unchanged for over 20 years. Several novel therapies, mostly targeting neomorphic/activating recurrent mutations found in AML patients, have only recently been approved following encouraging results, thus providing the first evidence of a more precise and personalized approach to AML therapy. Rewired metabolism has been described as a hallmark of cancer and substantial evidence of its role in AML establishment and maintenance has been recently accrued in preclinical models. Interestingly, unique metabolic changes are generated by specific AML recurrent mutations or in response to diverse AML therapies, thus creating actionable metabolic vulnerabilities in specific patient groups. In this review we will discuss the current evidence supporting a role for rewired metabolism in AML pathogenesis and how these metabolic changes can be leveraged to develop novel personalized therapies.

Keywords: acute myeloid leukemia; drug resistance; leukemic stem cell; metabolism; personalized therapy.

Figure 1

Metabolic pathways potentially associated with resistance to currently used pharmacological agents or specific genetic signatures. Chemotherapeutics or targeted therapy drugs currently in use for AML (in green) are presented next to the cytosolic (in blue) or mitochondrial (in red) metabolic pathway whose activity has been reported to be modulated upon treatment with respective compound or which has been associated with drug resistance. Genetic markers associated to changes in certain metabolic pathways are given in yellow.