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.

Keywords: IDH1/2 mutations; TET2 mutations; myeloid malignancies; nicotinamide; venetoclax.

Figure 1

View at a glance of the landscape of the metabolic interactions between genes and pathways discussed in the manuscript. On the left, the intrinsic apoptotic pathway highlighted by BCL-2 as the pivotal player (targeted by Venetoclax) and the interaction with BAX and BIM to initiate the caspases cascade to trigger apoptosis. On the right, the interaction between the Krebs cycle (TCA), the convergence of IDH1/2 generating α-ketoglutarate, 2-hydroxyglutarate and the TET family of genes, which finally impacts DNA methylation. Included are also the available drugs used to target the depicted pathways. On the top, in relapsed/refractory (R/R) acute myeloid leukemia (AML), the interconnection between the increase in NAD metabolism generated by alteration of oxidative phosphorylation and Venetoclax resistance is shown together with proposed actionable target agents (e.g., KPT-9274) inhibiting Nicotinamide Phosphoribosyltransferase (NAMPT). Images were generated using BioRender.

Figure 2

TET functions and their alterations in myeloid malignancies. DNA methyltransferases (DNMTs) initiate cytosine methylation with conversion to 5-methylcytosine (5-mc). TET proteins progressively oxidize 5-mC to 5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-FoC), and 5-carboxylcytosine (5-CaC) creating a pool of TET-oxidized products (TDOP). 5-hmC can be reverted to cytosine via passive dilution while 5-FoC and 5-CaC via thymine DNA glycosylase-mediated base excision repair. Somatic TET2 mutations create an imbalance in cellular DNA methylation through the disruption of the aforementioned mechanism with alteration of chromatin and thereby consequences on expression of genes regulating cell division and self-renewal. Images were generated using BioRender.