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Review
. 2019 Apr;2(2):e1139.
doi: 10.1002/cnr2.1139. Epub 2018 Oct 7.

Metabolic underpinnings of leukemia pathology and treatment

Travis Nemkov  1 , Angelo D'Alessandro  1 , Julie A Reisz  1
Affiliations
Review

Metabolic underpinnings of leukemia pathology and treatment

Travis Nemkov et al. Cancer Rep (Hoboken). 2019 Apr.

Abstract

Background: Carcinogenic transformation of white blood cells during hematopoiesis leads to the development of leukemia, a cancer characterized by incompetent immune cells and a disruption of normal bone marrow function. Leukemias are diverse in type, affected population, prognosis, and treatment regimen, yet a common theme in leukemia is the dysregulated metabolism of leukemic cells and leukemic stem cells with respect to their noncancerous counterparts.

Recent findings: In this review, we highlight current findings that elucidate metabolic traits unique to the four major types of leukemia, which confer carcinogenic survival but can be potentially exploited for therapeutic intervention. These metabolic features can work in conjunction with or be independent of unique aspects of the bone marrow microenvironment that can also influence cell survival and proliferation, thus sustaining carcinogenesis.

Conclusion: Deepening our understanding of the interactions of leukemias with their niche environments in vivo will inform future treatments for leukemia, particularly for those that are refractive to tyrosine kinase inhibitors and other therapeutic mainstays.

Keywords: leukemia; mass spectrometry; metabolism; metabolomics; stable isotope tracing; tumor microenvironment.

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Conflict of interest statement

Although unrelated to the contents of the manuscript, the authors disclose that AD and TN are members of Omix Technologies, Inc.

Figures

Figure 1
Figure 1
Overview of hematopoiesis and transformation. Hematopoietic stem cells (HSCs) possess self‐renewing capacity and are maintained as a small population. Generation of multipluripotent progenitor (MPP) cells devoid of self‐renewal, but with active proliferation, marks the path toward differentiation to ultimately form the cellular components of blood. Carcinogenic transformation at the HSC stage generates leukemic stem cells (LSCs); transformation of mature or immature cells at points downstream generates leukemic cells. Shown here is an overview of metabolic features of the leukemia types. Abbreviations: ATP, adenosine triphosphate; CE, cholesterol ester; CoQ10, coenzyme Q10; FA, fatty acid; FAA, fatty acid amide; GLS, glutaminase; GSH, reduced glutathione; HIF‐1α, hypoxia‐inducible factor 1α; NAD, nicotinamide adenine dinucleotide; PC, phosphatidylcholine; PGF2α, prostaglandin F2α; PPP, pentose phosphate pathway; R‐2HG, (R)‐2‐hydroxyglutarate; RNS, reactive nitrogen species; ROS, reactive oxygen species; SM, sphingomyelin; TG, triglyceride; TxB3, thromboxane B3
Figure 2
Figure 2
Metabolic alterations observed in CLL cells. A, Flux through glutaminolysis is increased as evidenced by decreased Gln and Glu, elevated ala, and increased expression of glutaminase and glutamine synthetase. Coculturing with stroma increases TCA cycle activity in CLL cells. B‐CLL cells have lower levels of cystine and the xCT cystine transporter; experimental evidence suggests that the stroma can regulate CLL redox homeostasis by reducing the cystine disulfide to cysteine, which enters cells and is utilized for glutathione biosynthesis
Figure 3
Figure 3
Metabolic alterations observed in CD‐34+ CML cells: Increased fatty acid oxidation leads to elevated levels of acylcarnitines and increased enrichment of TCA cycle metabolites and amino acids from stable isotope labeled palmitate. TCA flux is also increased via the enhanced activity of anaplerotic enzyme pyruvate carboxylase
Figure 4
Figure 4
Metabolic features of AML cells. A, Mutant isocitrate dehydrogenase (IDH) generates oncometabolite (R)‐2‐hydroxyglutarate from a‐ketoglutarate. B, Hallmarks of drug‐resistant AML cells include a reliance on glutamine to fuel glutathione (GSH) biosynthesis and pyrimidine synthesis. Additionally, drug‐resistant cells have elevated pentose phosphate pathway (PPP) activity particularly of rate‐limiting enzyme glucose 6‐phosphate dehydrogenase (G6PDH)
Figure 5
Figure 5
Glucose metabolism in ALL cells. Gatekeeper transcription factors PAX5 and IKZF1 limit ATP production through glycolysis to prevent transformation. Together, genetic lesions and Bcr‐Abl rewire metabolism to allow for rapid glycolytic flux. PP2A is required by ALL cells and activates the PPP to sustain redox homeostasis alongside rapid proliferation
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