The Interactome between Metabolism and Gene Mutations in Myeloid Malignancies

Abstract

The study of metabolic deregulation in myeloid malignancies has led to the investigation of metabolic-targeted therapies considering that cells undergoing leukemic transformation have excessive energy demands for growth and proliferation. However, the most difficult challenge in agents targeting metabolism is to determine a window of therapeutic opportunities between normal and neoplastic cells, considering that all or most of the metabolic pathways important for cancer ontogeny may also regulate physiological cell functions. Targeted therapies have used the properties of leukemic cells to produce altered metabolic products when mutated. This is the case of IDH1/2 mutations generating the abnormal conversion of α-ketoglutarate (KG) to 2-hydroxyglutarate, an oncometabolite inhibiting KG-dependent enzymes, such as the TET family of genes (pivotal in characterizing leukemia cells either by mutations, e.g., TET2, or by altered expression, e.g., TET1/2/3). Additional observations derive from the high sensitivity of leukemic cells to oxidative phosphorylation and its amelioration using BCL-2 inhibitors (Venetoclax) or by disrupting the mitochondrial respiration. More recently, nicotinamide metabolism has been described to mediate resistance to Venetoclax in patients with acute myeloid leukemia. Herein, we will provide an overview of the latest research on the link between metabolic pathways interactome and leukemogenesis with a comprehensive analysis of the metabolic consequences of driver genetic lesions and exemplificative druggable pathways.

Vitamin C Deficiency in Patients With Acute Myeloid Leukemia

“…Vitamin C has been shown to play a significant role as an epigenetic anticancer agent able to reprogram HSCs ( 20 ), suggesting that its administration may help to restore normal hematopoiesis ( 40 ). The role of vitamin C as an anti-cancer agent has long been debated ( 11 , 22 ) and although recent reports have suggested it as a novel metabolic tumor suppressor, results on its clinical benefits remain controversial.…”

The Anti-Leukemia Effect of Ascorbic Acid: From the Pro-Oxidant Potential to the Epigenetic Role in Acute Myeloid Leukemia

“…Furthermore, TET3 upregulation has also been invoked as a potential mechanism compensating the general TET2opathy of myeloid disorders, and has been linked to better survival outcomes in MDS with TET2 deficiency. Perhaps, ascorbate treatment may rescue the fraction of patients not able to contra-balance TET2 loss, thereby improving their dismal clinical outcomes (Gurnari et al, 2021(Gurnari et al, , 2022.…”

Lysosome-mediated chemoresistance in acute myeloid leukemia

“…Recently, new targeted drugs have been approved, incorporating the notion of personalised treatments for AML. Continuous assessment of newly approved drugs over time will provide valuable complete efficacy and safety data that will result in an optimal drug regime, as current clinical benefit is controversial [3,4] . Thus, acquisition of new biological insight in AML pathophysiology represents an unmet need necessary to expand the targetable therapeutic mechanism repertoire to overcome chemoresistance and, then, significantly improve clinical outcomes for AML patients.…”

“…Primary and secondary chemoresistance have been widely explored using conventional approaches, searching for gene mutations, chromosomal aberrations, and dysregulated signaling pathways [ 5 - 8 ] . Changes in the multidrug resistance gene family affect the intracellular concentration of drugs by either reducing the active transport into the tumor cells or increasing the efflux out to the extracellular space.…”