Metabolic dependencies and vulnerabilities in leukemia

Abstract

Leukemia cell proliferation requires up-regulation and rewiring of metabolic pathways to feed anabolic cell growth. Oncogenic drivers directly and indirectly regulate metabolic pathways, and aberrant metabolism is central not only for leukemia proliferation and survival, but also mediates oncogene addiction with significant implications for the development of targeted therapies. This review explores leukemia metabolic circuitries feeding anabolism, redox potential, and energy required for tumor propagation with an emphasis on emerging therapeutic opportunities.

Keywords: Warburg effect; glycolysis; leukemia; metabolism; mitochondria; targeted therapy.

Figure 1.

Glycolysis and pentose phosphate pathway. Catabolically, glycolysis converts glucose to pyruvate ultimately producing lactate, or acetyl-CoA in the TCA cycle for mitochondrial oxidative phosphorylation. Anabolically, glycolysis generates metabolic precursors for serine biosynthesis and supports redox potential and nucleotide biosynthesis via the pentose phosphate pathway. Most leukemias are highly dependent on glycolysis and can be targeted using glycolytic inhibitors.

Figure 2.

Mitochondrial metabolic therapeutic targets. The mitochondria also serves as a major energy factory in leukemia cells in support of targeting oxidative phosphorylation with biguanide drugs (metformin and phenformin) and mitochondrial protein biosynthesis with tigecycline. Leukemia cells, which are highly dependent on arginine–creatine metabolism, are sensitive to cyclocreatine-mediated inhibition of creatine kinase. Activation of the intrinsic apoptosis pathway with BH3 mimetic drugs such as ABT199 activate the BAK–BAX complex to introduce pores in the mitochondrial membrane, enhancing the activity of mitochondrial metabolism-targeting drugs.

Figure 3.

Nucleotide metabolism. Purine and pyrimidine biosynthesis are central to DNA replication and can be inhibited with antimetabolite drugs. In addition, the purine degradation activity of NT5C2, which contributes to resistance to 6-MP, sensitizes leukemia cells to inhibition of purine biosynthesis with mizoribine.

Figure 4.

Metabolic targeting of epigenetic mechanisms in leukemia. TET enzymes, which mediate DNA demethylation, use α-ketoglutarate as a substrate and ascorbate as a cofactor and are inhibited in AML and myeloproliferative disorders as a result of loss-of-function mutations in TET2 or because of 2HG produced by neomorphic mutations in the IDH1 and IDH2 genes. Small molecule inhibitors of mutant IDH1 and IDH2, and vitamin C supplementation can abrogate the production of 2HG or enhance TET2 activity, respectively, restoring DNA methylation patterns and myeloid cell differentiation.