Insights on Metabolic Reprogramming and Its Therapeutic Potential in Acute Leukemia

Abstract

Acute leukemias, classified as acute myeloid leukemia and acute lymphoblastic leukemia, represent the most prevalent hematologic tumors in adolescent and young adults. In recent years, new challenges have emerged in order to improve the clinical effectiveness of therapies already in use and reduce their side effects. In particular, in this scenario, metabolic reprogramming plays a key role in tumorigenesis and prognosis, and it contributes to the treatment outcome of acute leukemia. This review summarizes the latest findings regarding the most relevant metabolic pathways contributing to the continuous growth, redox homeostasis, and drug resistance of leukemia cells. We describe the main metabolic deregulations in acute leukemia and evidence vulnerabilities that could be exploited for targeted therapy.

Keywords: acute leukemia; metabolism; targeted therapy.

Figure 1

Transcriptional repression of glucose metabolism by metabolic gatekeepers prevents B-cell transformation and is lost during oncogenic signaling. (A) Gatekeeper transcription factors (PAX5, IKZF1) limit glucose consumption and the production of metabolites that fuel the tricarboxylic acid cycle (TCA), thus limiting the energy (ATP) production necessary for neoplastic transformation; (B) Genetic alterations leading to loss of PAX5 or IKZF1 gatekeeper functions allow an unrestricted consumption of glucose (glycolytic flux) and sufficient energy production to permit transformation. In B cells, protein phosphatase 2A (PP2A) is required in order to further enhance glucose utilization, which is also through the PPP pathway. Solid arrows indicate activity of the pathway; dashed lines indicate inhibited or weak activities. GLUT: glucose transporter; G-6-P: glucose-6-phosphate; GA-3P: glyceraldehyde-3-phosphate; 3-PG: 3-phosphoglycerate; 6-PGL: 6-phosho-gluconolactone; PEP: phosphoenolpyruvate; Pyr: Pyruvate; α-KG: alpha-ketoglutarate; Glu: glutamine; Cys: cysteine; Gly: glycine; Ser: serine; ribulose-5-P: ribulose-5-phosphate; PRPP: phosphoribosyl pyrophosphate; OAA: oxaloacetate; PPP: pentose phosphate pathway; TCA: tricarboxylic acid cycle; OXPHOS: oxidative phosphorylation; ETC: electron transport chain.

Figure 2

Oncogenic functions of BCAT1 are highly dependent on mutational and cellular context. (A) In AML, LICs showing high expression of BCAT1 but low levels of EZH2 (IDH1/2wt, TET2wt, EZH2wt genotype), BCAT1 catalyzes BCAA deamination with depletion of α-KG. This leads to a reduced activity of α-KG-dependent histone and DNA demethylases and α-KG-dependent dioxygenases with DNA hypermethylation and stabilization of HIF-1α; (B) In the transition from myeloproliferative diseases (MPN; PV, ETP, PF) to acute leukemia, EZH2 loss reactivates BCAT1 expression, while oncogenic RAS (NrasG12D) increases glutamine (Gln) uptake and consumption. This leads to enhanced BCAT1-catalyzed BCKA reamination to BCAAs and subsequent mTORC1 activation. The activity of α-KG-dependent enzymes is also enhanced as well as Glu-dependent processes such as nucleotide synthesis, redox balance, and protein synthesis. All these events contribute to myeloid transformation. Solid arrows indicate the activity of the pathway, dashed lines indicate inhibited or weak activities. GLS: glutaminase; Gln: glutamine; Glu: glutamate; BCAAs: branched chain amino acids; BCKA: branched chain α-keto acids; α-KG: apha-ketoglutarate; TET2: Ten-eleven translocation 2 demethylase; mTOR: Mammalian target of rapamycin; NEAA: non-essential amino acids; LICs: leukemia-initiating cells; PV: polycythemia vera; ETP: essential thrombocytopenia; PF: primary myelofibrosis.