Metabolic reprogramming in childhood acute lymphoblastic leukemia

Abstract

The first observations of altered metabolism in malignant cells were made nearly 100 years ago and therapeutic strategies targeting cell metabolism have been in clinical use for several decades. In this review, we summarize our current understanding of cell metabolism dysregulation in childhood acute lymphoblastic leukemia (cALL). Reprogramming of cellular bioenergetic processes can be expected in the three distinct stages of cALL: at diagnosis, during standard chemotherapy, and in cases of relapse. Upregulation of glycolysis, dependency on anaplerotic energy sources, and activation of the electron transport chain have all been observed in cALL.While the current treatment strategies are tackling some of these aberrations, cALL cells are likely to be able to rewire their metabolism in order to escape therapy, which may contribute to a refractory disease and relapse. Finally, here we focus on novel therapeutic approaches emerging from our evolving understanding of the alterations of different metabolic networks in lymphoblasts. K E Y W O R D SBioenergetics, cALL, cell metabolism, therapy

The Protozoan Inhibitor Atovaquone Affects Mitochondrial Respiration and Shows In Vitro Efficacy Against Glucocorticoid-Resistant Cells in Childhood B-Cell Acute Lymphoblastic Leukaemia

“…The interplay between mTOR complex 1 (mTORC1) and mitochondrial function and cell metabolism is well-documented (40). Activation of the AKT-mTOR pathway, which is altered in up to one third of children with T-ALL (41), may lead to considerable changes in cell metabolism and upregulation of glycolysis (4,42). Investigating the potential effect of Ato on this pathway was beyond the scope of our study.…”

“…Altered cancer cell metabolism, described nearly a century ago by Warburg (1), has gone a long way from an intriguing scientific observation to a validated drug target in the clinic. Initially believed to serve as an alternative energy source for the rapidly dividing cancer cells, "Warburg's effect" of oxidative glycolysis is now considered an effective means of metabolic rewiring which provides multiple precursors for key biosynthetic pathways (2)(3)(4). Excellent examples showing alterations in cell bioenergetics and the clinical use of certain metabolic vulnerabilities come from acute lymphoblastic leukaemia (ALL) (4).…”

Insights on Metabolic Reprogramming and Its Therapeutic Potential in Acute Leukemia

“…In addition, lactate production is very high even under normoxic conditions, and the inhibition of glycolysis in these cells induces apoptosis, indicating dependence on elevated aerobic glycolysis for survival. Thus, OXPHOS is reduced in these cells, and putative non neutral mutations in subunits of the OXPHOS machinery encoded by mitochondrial DNA (mtDNA) have been described in ALL samples, possibly contributing to altered ETC activity [28][29][30]. The molecular drivers causing the metabolic shift to aerobic glycolysis are diverse and probably act synergistically.…”

Insights on the Interplay between Cells Metabolism and Signaling: A Therapeutic Perspective in Pediatric Acute Leukemias

“…However, most of the metabolic dysfunctions are caused by aberrant expression of genes and/or proteins not directly involved in cell metabolism. In 40%-50% of patients with childhood ALL, mutations in RAS pathway, involved in cell growth, survival and differentiation, can be found, and these are correlated with a poor prognosis [32,33]. Intriguingly, marked changes in metabolic homeostasis are found in RAS-mutated ALL patients [34], with a general switch to a hyperglycolytic phenotype accompanied by a decrease in mitochondrial OXPHOS rate [35].…”

“…Nevertheless, it is also critical to integrate data from epigenetic studies, as the control of gene expression is directly or indirectly linked to leukemogenesis and metabolic response, as demonstrated by the use of the histone deacetylase (HDAC) inhibitor Vorinostat. This drug is able to reexpress a number of deregulated genes involved in GC response, nucleotide biosynthesis and folate metabolism, and specifically these metabolic genes resensitize cell response to Prednisolone [33,50,51].…”