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Oncogenic Mechanisms and Therapeutic Targeting of Metabolism in Leukemia and Lymphoma

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Oncogenic Mechanisms and Therapeutic Targeting of Metabolism in Leukemia and Lymphoma Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Oncogenic Mechanisms and Therapeutic Targeting of Metabolism in Leukemia and Lymphoma Maximilian Stahl,1 Zachary D. Epstein-Peterson,1 and Andrew M. Intlekofer Department of Medicine and Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA Correspondence: [email protected] Leukemias and lymphomas acquire the capacity for unrestrained cell growth and proliferation in conjunction with loss of responsiveness to molecular programs that promote terminal differentiation. Malignant cells generate the building blocks required for rapid cell division through both increased acquisition of nutrients from the environment and reprogrammed intermediary metabolism to shunt these molecules into producing the protein, lipids, and nucleic acids that comprise cell biomass. These accelerated metabolic processes require energy in the form of ATP and reducing equivalents in the form of NADPH, which power biosynthetic reactions and buffer oxidative stress encountered by the metabolically active cancer cell. Cancer-associated metabolic alterations can also promote accumulation or de- pletion of specific metabolites that directly regulate cell fate and function, thereby coupling metabolic reprogramming to dedifferentiation and stemness. This review will focus on the mechanisms by which leukemia and lymphoma cells rewire cellular metabolism to support: (1) bioenergetics, (2) biomass accumulation, (3) redox balance, and (4) differentiation block- ade. We will further highlight examples of how specific pathways of leukemia and lymphoma metabolism confer therapeutic vulnerabilities that can be targeted to inhibit growth or promote differentiation. t a fundamental level, cancer is a problem of mechanisms (Palm and Thompson 2017). www.perspectivesinmedicine.org Ahijacked cellular metabolism (Vander Hei- Such unrestricted nutrient uptake is critical to den et al. 2009). Normally, metazoan cells build the cellular biomass (protein, lipids, nu- require “permission” from growth factors, cyto- cleic acids) necessary for rapid cell doubling kines, hormones, or antigen/costimulatory re- (Fig. 1). Because the availability of specific nu- ceptors to increase nutrient uptake. All cancers, trients in the environment does not precisely including leukemias and lymphomas, acquire match the necessary outputs, cancer cells must the capacity for cell-autonomous uptake of nu- rewire metabolic circuits to rapidly convert trients that circumvents normal regulatory available nutrients into precursor metabolites 1These authors contributed equally to this work. Editors: Michael G. Kharas, Ross L. Levine, and Ari M. Melnick Additional Perspectives on Leukemia and Lymphoma: Molecular and Therapeutic Insights available at www.perspectivesinmedicine.org Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a035477 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press M. Stahl et al. Protein ATP Bioenergetics Biomass Lipids GTP Nucleic acids Reprogrammed cancer metabolism NAD+(H) Chromatin/ NADP+(H) Redox balance Differentiation epigenetics FAD(H2) Figure 1. Key functions of reprogrammed cancer metabolism. Leukemias and lymphomas reprogram cellular metabolism to meet the anabolic demands of malignant growth and proliferation. Glycolysis and mitochondrial oxidative phosphorylation provide energy in the form of ATP and GTP (Bioenergetics). Metabolic intermediates are shunted into biosynthetic pathways that produce the protein, lipids, and nucleic acids required for cell doubling and division (Biomass). Malignant cells require increased regeneration of NAD+ to enable oxidative biosynthetic reactions (e.g., nucleotides), as well as increased production of NADPH to fuel reductive biosyn- thetic reactions (e.g., lipids) and buffer oxidative stress (redox balance). Deregulation of specific metabolites or metabolic pathways can also disrupt chromatin marks, resulting in impaired differentiation and/or enhanced self-renewal (differentiation). (ATP) Adenosine triphosphate, (GTP) guanosine triphosphate, (NAD) nicotin- amide adenine dinucleotide, (NADP) nicotinamide adenine dinucleotide phosphate, (FAD) flavin adenine dinucleotide. that can be used to synthesize the macromole- ate the cytosolic NAD+ required to maintain cules that comprise cell biomass. This intensive glycolytic flux. However, despite the ability of metabolic activity requires energy in the form of glycolysis to provide adequate ATP, mitochon- adenosine triphosphate (ATP) and reducing drial electron transport remains essential for equivalents in the form of nicotinamide adenine virtually all cancer cells in order to regenerate dinucleotide phosphate (NADPH) to fuel bio- the electron acceptors (NAD+) required for synthetic reactions (Fig. 1). macromolecular biosynthesis (Hosios and Van- As first described by Otto Warburg almost der Heiden 2018). Moreover, certain cancer cells 100 years ago, most cancer cells rapidly ferment without high glycolytic flux, including leukemic glucose to lactate regardless of oxygen availabil- stem cells and a subset of diffuse large B-cell ity (Warburg 1924, 1956). A high rate of glycol- lymphoma (DLBCL), appear to be particularly ysis by cancer cells serves at least two important dependent on OXPHOS, which may be related www.perspectivesinmedicine.org functions, which are often difficult to dissociate to their preferential oxidation of alternative fuels mechanistically: (1) ATP production and (2) that can only generate ATP through the mito- generation of precursor molecules and reducing chondria (Caro et al. 2012; Ye et al. 2016; Jones equivalents required for biosynthesis of macro- et al. 2018). molecules (Fig. 2; Vander Heiden et al. 2009). Proliferating cells must double their biomass Surprisingly, the limited amount of ATP (max- in order to divide, which requires assembling all imum of 2 ATP per glucose) generated by of the proteins, lipids, and nucleic acids that glycolysis can be sufficient to support cell pro- comprise the cell (Fig. 1; Hosios et al. 2016). A liferation in highly glycolytic cancer cells with- subset of carbohydrates, amino acids, lipids, and out a requirement for additional ATP generated nucleotides can be acquired from the microen- by mitochondrial oxidative phosphorylation vironment for direct incorporation into macro- (OXPHOS) (Birsoy et al. 2015; Sullivan et al. molecules, However, a major function of cancer 2015). Running glycolysis at a high rate appears metabolism involves conversion of available nu- to necessitate the Warburg effect, which drives trients, such as glucose and glutamine, into met- conversion of pyruvate to lactate by lactate de- abolic intermediates that can be directed into hydrogenase (LDH) in order to rapidly regener- macromolecular biosynthetic pathways (Fig. 2; 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a035477 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Metabolic Hallmarks of Leukemia and Lymphoma Glucose Redox NADPH Ribose PPP Redox Nucleotides Folate/ NADPH one-carbon Glycolysis Serine pathway SAM Protein cycles Differentiation Redox Bioenergetics NAD+ ATP Lactate Pyruvate Lipids Acetyl-CoA Differentiation OXPHOS Citrate Bioenergetics TCA cycle ATP (GTP) Acetate Fumarate Succinate αKG Differentiation Glutamine GSH Redox Aspartate Nucleotides AAs Protein Figure 2. Simplified overview of metabolic pathways in leukemia and lymphoma. Altered and/or enhanced glycolysis, pentose phosphate pathway (PPP), serine biosynthetic pathway, folate/one-carbon cycles, tricarbox- ylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), lipid synthesis, and amino acid (AA) metabolism support bioenergetics (red), biomass accumulation (green), redox balance (blue), and differentiation blockade (purple). Most precursors, products, cofactors, and enzymes are intentionally absent for simplicity. (ATP) Adenosine triphosphate, (GTP) guanosine triphosphate, (NAD) nicotinamide adenine dinucleotide, (NADPH) nicotinamide adenine dinucleotide phosphate, (SAM) S-adenosyl methionine, (αKG) alpha-ketoglutarate, (GSH) reduced glutathione. www.perspectivesinmedicine.org Vander Heiden and DeBerardinis 2017). Glyco- Analogous to enhanced glucose consump- lytic intermediates provide a key pool of sub- tion and glycolytic flux, most leukemias and strates for biosynthetic reactions: The pentose lymphomas exhibit increased uptake and con- phosphate shunt produces ribose sugars for nu- sumption of glutamine, or glutaminolysis (Fig. cleotide biosynthesis; dihydroxyacetone phos- 2; Wise and Thompson 2010). Glutamine phate can be converted into glycerol for lipid serves as a nitrogen donor for nucleotide syn- biosynthesis; serine biosynthesis from 3-phos- thesis and for transamination reactions to gen- phoglycerate operates in conjunction with the erate nonessential amino acids. Likewise, glu- folate pathway to form one-carbon units for tamine-derived aspartate functions as a key nucleotide production; and multiple glycolytic building block for nucleotide biosynthesis intermediates can be used for the synthesis of (Wise and Thompson 2010). Glutamine also nonessential amino
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