Exploring the Metabolic Landscape of AML: From Haematopoietic Stem Cells to Myeloblasts and Leukaemic Stem Cells

Abstract

Despite intensive chemotherapy regimens, up to 60% of adults with acute myeloid leukaemia (AML) will relapse and eventually succumb to their disease. Recent studies suggest that leukaemic stem cells (LSCs) drive AML relapse by residing in the bone marrow niche and adapting their metabolic profile. Metabolic adaptation and LSC plasticity are novel hallmarks of leukemogenesis that provide important biological processes required for tumour initiation, progression and therapeutic responses. These findings highlight the importance of targeting metabolic pathways in leukaemia biology which might serve as the Achilles' heel for the treatment of AML relapse. In this review, we highlight the metabolic differences between normal haematopoietic cells, bulk AML cells and LSCs. Specifically, we focus on four major metabolic pathways dysregulated in AML; (i) glycolysis; (ii) mitochondrial metabolism; (iii) amino acid metabolism; and (iv) lipid metabolism. We then outline established and emerging drug interventions that exploit metabolic dependencies of leukaemic cells in the treatment of AML. The metabolic signature of AML cells alters during different biological conditions such as chemotherapy and quiescence. Therefore, targeting the metabolic vulnerabilities of these cells might selectively eradicate them and improve the overall survival of patients with AML.

Keywords: acute myeloid leukaemia; cancer metabolism; leukaemic stem cells; metabolic plasticity; metabolic targeting.

Graphical Abstract

Figure 1

Conventional chemotherapy is ineffective to target and eliminate LSCs, leading to AML relapse. In the normal haematopoietic system, HSCs differentiate into myeloid progenitor cells and eventually produce mature haematopoietic cells. In AML these HSCs acquire genetic mutations which impair the differentiation process and convert them to LSCs. These cells acquire self-renewal ability and produce leukaemic blasts in the bone marrow and other organs. Although the current treatment strategies eliminate leukaemic blasts, they are unable to destroy LSCs completely which will cause AML relapse. BM, Bone marrow; HSCs, Haematopoietic stem cells; LSCs, Leukaemic stem cells.

Figure 2

Principal dysregulated metabolic pathways in AML. Carbohydrates and amino acids are two main sources of energy for AML cells which can be used in other metabolic pathways. Red, green, and purple texts are critical compounds in the relevant pathways. Brown-cream rectangles, indicating the crucial metabolic processes required for cell survival and proliferation. GLUT, glucose transporter; G6P, glucose-6-phosphate; R5P, ribose-5-phosphate; F1P, fructose-1-phosphate; PEP, phosphoenolpyruvate; G3P, glycerol-3-phosphate; OAA, oxaloacetate; α-KG, α-ketoglutarate; PPP, pentose phosphate pathway; ALAT, alanine transferase; GSH, glutathione; GSR, glutathione-disulfide reductase; GPX1, glutathione peroxidase 1; FA, fatty acid; GLS, glutaminolysis; OXPHOS, oxidative phosphorylation.

Figure 3

The tumour microenvironment alters the metabolic profile of different types of haematopoietic cells. Mature haematopoietic cells and normal HSCs maintain their genome integrity and therefore regulate their metabolic profile in a balanced manner (green cells). In contrast, immature leukaemic blasts and LSCs with an unstable genome display dysregulated metabolic profiles (purple cells). PB, peripheral blood; BMME, bone marrow microenvironment; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid cycle; ETC, electron transfer chain; HSCs, haematopoietic stem cells; FAO, fatty acid oxidation; AAs, amino acids; LSCs, leukaemic stem cells.