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.
Highlights
Acute leukemia arises from the malignant transformation of myeloid or lymphoid hematopoietic progenitor cells
Numerous factors are at the heart of the metabolic rewiring that occurs in tumors, amongst which a key role is played by signaling pathways frequently deregulated in cancer such as avian myelocytomatosis viral oncogene homolog (MYC), neurogenic locus notch homolog protein 1 (NOTCH1), Fms Related Receptor Tyrosine Kinase 3 (FLT3), rat sarcoma viral oncogene homolog/mitogen-activated protein kinase (RAS/MAPK), and the phosphoinositide 3kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mechanistic target of rapamycin pathways [6]
A small portion of Trp is used for protein biosynthesis and neurotransmitter production, the majority of the Trp pool is degraded in the kynurenine pathway (KP), which generates several metabolites mainly involved in immunomodulation
Summary
Acute leukemia arises from the malignant transformation of myeloid or lymphoid hematopoietic progenitor cells. (as previously mentioned), increased aerobic glycolysis is a common trait in most AML and ALL cells, the rare LIC population manifests distinct metabolic features (at least in AML) compared to normal HSCs [21] These LICs are dependent on OXPHOS with a lower glycolytic reserve compared to mature (bulk) cancer cells; in addition, they show low levels of reactive oxygen species (ROS) and increased levels of glutathione (GSH), sensitivity to disruption of ETC, lack of glucose dependency for energy production, and reliance on amino acids for OXPHOS metabolism [12]. Loss of PP2A in B-cell leukemia blasts increases glucose utilization and glycolysis products including ATP and lactate, while decreasing PPP-dependent antioxidant protection These observations identify a gatekeeper function of the PPP in B-cell malignancies amenable for therapeutic intervention through the inhibition of PP2A and glucose-6-phosphate dehydrogenase (G6PD) [42]
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