Chapter 14: Metabolism of Hematologic Neoplastic Cells

HOMEOSTASIS

The canonical cell has significant bioenergetic needs for maintenance and homeostasis.⁶ Protein synthesis and maintenance of cellular membrane potentials consume most of the ATP produced under homeostatic conditions.⁷ In many differentiated or quiescent cells, it is believed that fatty acid oxidation provides the bulk of the energy, followed by the use of glucose. In this regard, mitochondrial respiration is essential for adult tissues and cells. It is notable, however, that specialized cell functions in the various organs could require different metabolic pathways. Glucocorticoid hormone-producing cells, for example, express specialized metabolic pathways. Although cardiac muscle cells depend heavily on fatty acid oxidation, skeletal muscle cells use glucose. The brain depends largely on glucose, but it can feed on ketone bodies under starved states. For differentiated cells, which are the bulk of cells in mammals, homeostasis drives the demand for nutrients, to “the availability of which are determined by feeding and interorgan (liver, muscle, and endocrine tissues) metabolic interplays. For example, lactate produced by exercising muscle circulates back to the liver and is processed via the Cori cycle to produce glucose.³ Glucose plasma level is tightly controlled by the pancreas, which produces insulin and glucagon, and by the liver (as well as kidney) that can produce glucose through gluconeogenesis.

CELL GROWTH: SIGNALING, NUTRIENTS, AND METABOLISM

Normal cell growth and proliferation are triggered by extracellular cues. Yeast cells, for example, only require the presence of nutrients to initiate cell growth or an increase in cell size.⁶ During this growth phase, nutrients are imported and channeled into biomass, which is largely comprised of ribosomes. It is estimated that ribosomes constitute more than 50 percent of cellular dry mass, and hence ribosome biogenesis is highly regulated and vitally important for cell growth and proliferation. Once a critical cell size (mass) is reached with a balanced nucleotide pool, DNA synthesis begins. Yeast cells sense nutrients, particularly glucose and glutamine, through pathways involving RAS and target of rapamycin complex 1 (TORC1), which silence transcriptional repressors of ribosome biogenesis.⁸ With nutrient deprivation, activation of these transcriptional repressors provides a metabolic checkpoint that restrains cells from growing in the absence of adequate bioenergetic support. Hence, the normal feedback loops couple nutrient availability with cell growth: no nutrients, no growth. The normal feedback loops can be artificially disrupted by deletion of transcriptional repressors of ribosomal biogenesis, rendering yeast mutants constitutively activated for growth. These mutants resemble mammalian cancer cells, which have mutations that drive autonomous cell growth with disregard for nutrient availability. The severance of nutrient sensing from growth signaling causes addiction of these yeast mutants to nutrients, such that deprivation of glucose or glutamine results in nonviable mutants. Similarly, cancer cells are addicted to nutrients.⁶

Cell growth in multicellular organisms requires additional cues in addition to the availability of nutrients. Mammalian cells live in a community of cells and are constantly bathed in nutrients derived from the circulation, but they do not proliferate unless there are appropriate cues from growth factors and the extracellular matrix. Mammalian cells can be envisioned as bioreactors that require at least two signals to grow: (1) growth factor and (2) nutrients.⁶ Cell growth is arrested in the absence of either growth factor or nutrients. Similar to yeast cells, metabolic checkpoints are critical to the growth of normal mammalian cells.

Growing cells largely depend on glucose, glutamine and other amino acids.⁹ Indeed, the core metabolic pathways including glycolysis, glutaminolysis, and the tricarboxylic acid (TCA) cycle link amino acid and glucose metabolism to lipogenesis and nucleotide synthesis (Fig. 14–1). Glycolysis starts with the transport of glucose into cells through several transporters, known as GLUTs, with SLC2A1 (GLUT1) being one that is coupled with cell growth stimulation. Once inside the cell, glucose is phosphorylated in an ATP-consuming step by hexokinases (HK) with HKII being stimulated by many growth signals and directly regulated by the MYC oncogene or the hypoxia inducible factor 1 alpha (HIF-1α). Glucose-6-phosphate (G6P) is used by the pentose phosphate pathway to produce ribose for nucleotide synthesis (Fig. 14–1) or converted to fructose phosphate via an isomerization reaction catalyzed by glucose phosphate isomerase (GPI).⁹ Fructose-6-phosphate is further phosphorylated with consumption of a second ATP through a rate-limiting step catalyzed by phosphofructokinase (PFK) to fructose-1,6-bisphosphate (F1,6BP). F1,6BP is converted by aldolase and an isomerase to the three-carbon phosphorylated molecule, glyceraldehyde 3-phosphate (GAP), which is oxidized and phosphorylated using inorganic phosphate by the dehydrogenase, GAPDH, to 1,3-bisphosphoglycerate. The energy gained by nicotinamide adenine dinucleotide (NAD+)-mediated oxidation and phosphorylation is released from 1,3-bisphosphoglycerate by phosphoglycerate kinase, which transfers the high-energy phosphate bond to adenosine diphosphate (ADP) to form ATP. The resulting 3-phosphoglycerate (3-PG) provides a substrate for serine and glycine synthesis, for the production of glycerol, or for the production of phosphoenol pyruvate (PEP) in glycolysis. Pyruvate kinase mediates the transfer of the high-energy phosphate bond from PEP to ADP producing ATP and pyruvate, which is the terminal substrate of glycolysis. Collectively, glycolysis uses ATP to charge up several intermediates for their transformations and uses NAD+ to oxidize intermediates and generate energy through new high-energy phosphate bonds with inorganic phosphate. Each glucose molecule results in the production of a net two ATP molecules from ADP through glycolysis.

Pyruvate, derived from glucose through glycolysis, from malate through malic enzyme or from alanine through transamination, could enter the mitochondria through specific transporters and be converted to acetyl-coenzyme A (CoA) by pyruvate dehydrogenase (PDH) (see Fig. 14–1).¹⁰ PDH activity can be attenuated by phosphorylation, mediated by PDH kinase (PDK), which is activated by hypoxia to divert glucose carbons away from the TCA cycle toward lactate production. Under aerobic conditions, acetyl-CoA combines with oxaloacetate coming from a complete turn of the TCA cycle to produce citrate, which can be extruded into the cytoplasm to participate in lipid synthesis or which can be converted to isocitrate in the TCA cycle. Isocitrate is further oxidized to α-ketoglutarate by isocitrate dehydrogenase (IDH) with the production of either nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide phosphate (NADPH) and release of a carbon dioxide molecule. There are three IDH isozymes with IDH1 being located in the cytosol, while IDH2 and IDH3 are in the mitochondrion. NADH in the mitochondrion contributes to the high-energy electrons that drive production of ATP through the electron transport chain. NADPH produced by cytosolic IDH1 or mitochondrial IDH2 could participate in reductive biosynthesis of fatty acids or nucleobases.

In addition to being a key TCA cycle intermediate at the crossroads of several metabolic pathways, a-ketoglutarate (or oxoglutarate) serves as a cofactor for many important oxygenases, such as those involved in the hydroxylation and degradation of the hypoxia inducible factors (HIFs), modification of ribosomes, or those involved in demethylation of DNA and histones.^11,12 Notably, glutamine can enter the TCA cycle at this junction. α-Ketoglutarate is further oxidized by oxoglutarate dehydrogenase (OGDH) to produce succinyl-CoA and carbon dioxide. Succinyl-CoA, which is also used for heme synthesis, is then converted to succinate with the production of a guanosine-5′-triphosphate (GTP) from guanosine-5′-diphosphate (GDP). Succinate is then converted to fumarate by succinate dehydrogenase (SDH), which is mutated in certain familial cancer syndromes. Fumarate hydratase (FH), which is also mutated in cancer syndromes, converts fumarate to malate that is, in turn, converted to oxaloacetate. Oxaloacetate can serve as a substrate for glutamate oxaloacetate transaminase (GOT) for the production of aspartate for nucleotide synthesis, or it can further cycle forward into the TCA cycle by combining with acetyl-CoA to form citrate, thus completing the TCA (citric acid or Krebs) cycle (see Fig. 14–1).

Glutamine also serves as a key metabolic substrate for growing cells (see Fig. 14–1). Glutamine is imported by membrane transporters, such as SLC1A5 or ASCT2.^13,14 Once in the cytosol, glutamine can contribute to protein synthesis or glucosamine or nucleobase biosynthesis by donating its nitrogen. Glutamine is further imported into the mitochondrion and converted to glutamate by glutaminase (GLS) with the release of ammonia. Glutamate is converted to α-ketoglutarate by either glutamate dehydrogenase (primarily in nongrowth states) or aminotransferases (GOT or glutamate pyruvate transaminase [GPT]). In this manner, glutamine serves as a major growth substrate for growing cells. Hence, the TCA cycle is a metabolic roundabout that uses carbons from glucose, glutamine, and fatty acids to generate carbon skeletons for biosynthesis, NADH for the production of ATP, or α-ketoglutarate for catalyzing key oxygenase reactions.

Oxidation of glucose, glutamine, and fatty acids produces energy for growing cells. On the other hand, synthesis of fatty acids and other building blocks require the reductive power of NADPH for bond formation. NADPH is produced from several well-characterized pathways, including the pentose phosphate pathway, malic enzyme, IDH, and the folate pathway.¹⁵ Glucose-6-phosphate dehydrogenase (G6PD) is well-known for its role in oxidation of G6P to 6-phosphogluconolactone and the concurrent reduction of NADP+ to NADPH, which contribute to an antioxidant state through maintaining reduced glutathione. Specifically, loss of G6PD function is associated with severe hemolytic anemia in patients who inherit hypomorphic alleles of G6PD (see Chap. 47). Malic enzyme mediates the oxidation of malate to pyruvate using nicotinamide adenine dinucleotide phosphate (NADP+), which is reduced to NADPH. IDH1 oxidizes isocitrate to α-ketoglutarate with the production of NADPH from NADP+. Lastly, it was recently documented that the folate pathway plays a major role in NADPH production through the oxidation of methylene-tetrahydrofolate (THF) to formyl-THF.¹⁵ The largest consumer of NADPH, on the other hand, involves fatty acid synthesis with reduction of glutathione following closely behind. Thus production of NADPH is critical for both biosynthesis and for redox homeostasis.

SIGNAL TRANSDUCTION: ONCOGENES, TUMOR SUPPRESSORS AND METABOLISM

Growth factors and nutrients drive the growth and proliferation of cells (Fig. 14–2 and Chap. 17). Growth factor engagement of a (usually dimeric) growth factor receptor triggers allosteric alterations that lead to autophosphorylation, in the case of the receptor tyrosine kinase family, or phosphorylation by Janus kinase in the cases of the hematopoietic cytokine receptor family. The phosphorylated receptor then recruits adaptor molecules that initiate a cascade of phosphorylation events, which culminate in the activation of concurrent pathways through phosphoinositol 3′-kinase (PI3K)/PTEN/AKT and RAS-RAF-ERK (extracellular regulated kinase) (Fig. 14–2). These cascades relay signals to mTOR complex, which is a vital hub for metabolic sensing and short-term post-transcriptional control of cell growth.¹⁶ mTOR, potentially coupled with additional outputs of the RAS-RAF-ERK pathway, also activates a genomic response to the growth signal. In essence, the mTOR pathway provides an immediate response to growth stimulus and nutrients followed thereafter by a transcriptional response that provides an increase in specific mRNAs needed for the production of new building blocks for the growing cell. The initial growth response occurs in cells that have a basal number of ribosomes, which serve to translate delayed early response genes. The cascade down the ERK pathway also activates the expression of early response genes such as FOS and MYC. The activation of MYC is probably mediated through the ERK-activation of Ets transcription factors, whose regulatory motifs are found in the MYC gene.¹⁷ Furthermore, ERK phosphorylates and stabilizes the MYC protein, enhancing ERK’s ability to drive a transcriptional response to growth.^18,19

The immediate sensing of nutrients is mediated through the adenosine monophosphate kinase (AMPK) and mTOR pathways, which, in turn, modulate cellular responses through phosphorylation of regulatory proteins (see Fig. 14–2).^9,16,20 In the presence of nutrients, the import of branched-chain amino acids is sensed through lysosomes to activate mTOR complex 1 (mTORC1). Import of glutamine, which is converted to glutamate, is thought to play an important role in activating mTOR through the antiporter, SLC7A1, which exports glutamate in exchange for leucine. Leucine is one of the most potent activators of mTORC1, which, in turn, phosphorylates key regulatory proteins to increase protein translation, mitochondrial biogenesis and respiration, glycolysis, and lipogenesis. Many of these effects are also mediated through mTORC1’s regulation of transcription factors such as PGC1α (mitochondrial biogenesis), HIF-1α (glycolysis), and SREBP (lipogenesis). mTORC1 also phosphorylates and inactivates the transcription factor TFEB, which is a master positive regulator of lysosome biogenesis.¹⁶ Presumably, inhibition of TFEB would also diminish the machinery involved in autophagy. Although mTORC1 also stimulates ribosome biogenesis, the mechanism by which this occurs is not yet known. Activation of the mTORC2 complex is less well defined, but mTORC2 is responsible for the subsequent activation of AKT that plays a critical role in activating glycolysis. Thus, growth factor signaling stimulates nutrient uptake that in turn activates mTOR to stimulate cell growth.

In nutrient-deprived states, the AMPK pathway regulates cellular responses that optimize energy production and diminish energy utilization pathways (see Fig. 14–2).^20,21 AMPK is allosterically altered by binding to adenosine monophosphate (AMP), which makes AMPK permissive for phosphorylation and activation by the tumor suppressor LKB1. The phosphorylated AMPK in turn phosphorylates and regulates many pathways involved in energy regulation. One of the earliest discoveries was that AMPK phosphorylates and inactivates acetyl-CoA carboxylase, which is involved in fatty acid synthesis. Thus, by diminishing lipogenesis, AMPK is able to inhibit an energy consuming process as well as inhibit cell growth by curbing lipogenesis. AMPK also attenuates protein synthesis through phosphorylation of RNA polymerase I, which is required for ribosome biogenesis. On the other hand, AMPK increases energy yield by stimulating glycolysis through phosphorylation and activation of PFK-2. AMPK stimulates mitochondrial biogenesis through phosphorylation of PGC1α and increases autophagy to recycle energy by phosphorylating ULK-1.²¹ Thus, increased AMPK activity conserves energy and maximizes energy production.

Together with posttranscriptional responses to growth signaling and nutrients, the nuclear transcriptional response is necessary to sustain the growth program through production of components of the ribosome and mRNAs that give rise to all other components of the cell. mTOR through its direct activation of specific transcription factors contributes to lipogenesis and mitochondrial biogenesis. Growth signaling also activates the MYC protooncogene, that regulates gene expression broadly to support cell growth and proliferation (see Figs. 14–2 and 14–3).¹⁹ Loss of function of Drosophila dMYC results in decreased cell and body size, a phenotype that underscores MYC’s role in cell growth.²² This phenotype mimics the loss of ribosome protein gene function in a group of mutant flies termed Minutes. Hence, Drosophila genetics links MYC to cell growth control. Furthermore, MYC is the only transcription factor capable of stimulating the activity of RNA polymerases I, II, and III, all of which are involved in ribosome biogenesis.

MYC dimerizes with its partner Max to bind a specific DNA sequence, termed E-box (CACGTG), and activate transcription.²³ It can also inhibit transcription partly through direct binding to Miz-1 and diminishing the expression of Miz-1 target genes, including the cyclin-dependent kinase (CDK) inhibitor p21 and genes involved in autophagy. Upon MYC activation, it is binding to proximal promoters accounts for most of it is transcriptional function in normal cells. When MYC is experimentally expressed at levels comparable to those found in cancers,¹⁹ excess MYC triggers p53-dependent checkpoints (see Fig. 14–3) that cause cell growth arrest or apoptosis. In multistep tumorigenesis, therefore, p53 is often lost, unleashing MYC’s full oncogenic potential. A high, unchecked level of MYC allows it to alter the transcriptome by amplifying selected target genes.²⁴ MYC was first shown to directly regulate genes involved in glycolysis, thereby linking an oncogenic transcription factor to metabolism.^6,19 Since these initial observations, high-throughput methods have mapped MYC to a broad swath of metabolic enzyme genes involved in glycolysis, glutaminolysis, and lipogenesis. MYC also directly regulates genes involved in mitochondrial biogenesis and the production of ribosomes. Specifically, genes highly induced by MYC include those involved in nucleolar function and ribosome biogenesis, such as Ncl, NPM1, fibrillarin, and NOP52. Collectively, these studies uncover MYC’s role as a central regulator of cell growth through coupling of energy metabolism with cellular biosynthetic processes.

Ribosome biogenesis is a critically important process for cell growth or cell mass accumulation.^25,26 Ribosomes are produced through RNAs that are transcribed by RNA polymerases I (rRNA [ribosomal RNA]), II (mRNA), and III (tRNAs [transfer RNAs] and small RNAs). rRNA is synthesized in the nucleolus from high copy numbers of rDNA, whose chromatin structure and transcription depends on nutrient availability. Under nutrient limitation, rDNA chromatin becomes less accessible, thereby restricting ribosome biogenesis.²⁶ Ribosomal proteins produced from mRNAs reenter the nucleolus, where components of ribosomes are assembled into mature ribosomal particles, which are exported to the cytosol. The production of rRNAs and proteins also provides an opportunity for bioenergetic sensing of adequate nutrients to support nucleic acid and protein synthesis required for growth. In this regard, specific ribosomal protein subunits (RPL5, RPL11, and others) can bind and inhibit MDM2 (mouse double minute 2 homolog), which binds to and mediates the degradation of p53.²⁵ Thus, it is surmised that ribosomal proteins in excess of rRNAs would activate p53, triggering checkpoints that block progression through the cell cycle, presumably in response to nutrient limitation sensed as an imbalance in rRNA and ribosomal protein synthesis.

In addition to sensing ribosome biogenesis, p53 also responds to genotoxic stresses by directly regulating metabolism (see Fig. 14–2). P53, in general, activates oxidative phosphorylation and inhibits glycolysis.²⁷ P53 can activate HK, which phosphorylates glucose in the first step of glycolysis, and stimulate TIGAR that shunts glucose to the pentose phosphate pathway through decreasing the levels of fructose-2,6-bisphosphate (F2,6BP), which allosterically activates PFK. P53 also increases the efficiency of mitochondrial function through induction of cytochrome c oxidase (SCO₂).²⁸ Overall, it appears that the normal function of p53 is to rewire metabolism to mitigate oxidative stress through increased production of NADPH and the antioxidant glutathione. Gain of p53 function through specific mutations, on the other hand, appears to alter metabolism through specific target genes that are involved in cholesterol biosynthesis or phospholipase function.^29,30

Other tumor suppressors are also involved in metabolism (see Fig. 14–2). PTEN negatively modulates PI3K, and hence its loss stimulates the PI3K pathway that is a potent regulator of cell metabolism through stimulation of glycolysis and activation of mTOR, AKT, MYC, and HIF.³¹ The tumor suppressor Lkb1, which is lost in some lung cancers, normally activates the AMPK pathway and diminishes lipogenesis.²¹ Loss of the von Hippel-Lindau (VHL) tumor suppressor activates HIF, which transcriptionally regulates glucose metabolism.³² In addition to any direct roles they play in regulating the cell-cycle machinery, tumor suppressors—similar to protooncogenes—also regulate metabolism. By coopting cellular responses to growth factor stimulation in the presence of nutrients, activation of oncogenes and disablement of tumor suppressors achieve coordinated posttranscriptional and transcriptional mobilizations that drive nutrients into ATP production and the building blocks for growing cells.

Growth factor stimulation also results in the production of metabolic wastes and toxins, including carbon dioxide, lactate, and reactive oxygen species (ROS) (Fig. 14–2). In this regard, various mechanisms have evolved to eliminate these wastes that accumulate as cells discard entropy into the environment after consuming “negative entropy” (macromolecules) to survive and grow. Carbon dioxide and protons are neutralized by carbonic anhydrase. Lactate is exported by monocarboxylate transporters.³³ Reactive oxygen species (ROS) are generated by the mitochondria and other cellular reaction pathways, such as via NADPH oxidases or disulfide bond formation.³⁴ ROS participates in signaling at ambient levels; however, very high levels of ROS result in oxidative cellular stress.^34,35 In particular, electrons leaking from the mitochondrial electron transport chain (ETC) contribute to a large fraction of cellular ROS.³⁵ Electrons are donated to the chain by NADH or succinate at mitochondrial complexes I, II, and III, which all generate ROS. Complexes I and II release ROS into the mitochondrial matrix, whereas complex III releases ROS into space on both sides of the inner mitochondrial membrane. Complex I accepts electrons from NADH, which is generated from TCA cycle oxidation, and passes them on to ubiquinone or coenzyme Q that also accepts electrons from succinate via complex II (SDH). Coenzyme Q then passes electrons to complex III, which, in turn, passes them onto cytochrome c. Finally, electrons are passed from cytochrome c to complex IV or cytochrome c oxidase that generates water from electrons, protons, and oxygen, which serves as the final electron acceptor. Upon accepting electrons at complexes I, III, and IV, a proton is pumped into the intermembrane space, creating a proton gradient across the inner mitochondrial membrane. The proton gradient is dissipated through complex V or ATP synthase with the generation of ATP from ADP. During the process of making ATP, leakage of electrons from complexes I, II, and III generates superoxide from oxygen.

Superoxide is highly reactive and could damage membranes and proteins if unattenuated. Hence, superoxide dismutases (SODs) have evolved to convert superoxide to hydrogen peroxide, which is, in turn, neutralized by catalases and converted to water and oxygen. In addition to enzymatic ROS neutralizers, the family of peroxiredoxins also plays an important role in titrating mitochondrial and cytosolic ROS by neutralizing hydrogen peroxide. Because oxidative stress imposed by ROS is a part of normal metabolism, a system of cellular response to this stress has evolved. Immediate response to ROS is mediated by SOD, catalase, peroxiredoxins, and glutathione. A sustained response to ROS is mediated chiefly through NRF2, which is a transcription factor that is negatively regulated by KEAP1, a protein that is directly inhibited by oxidative modification of sensitive cysteine residues.³⁶ NRF2 activates many genes involved in redox homeostasis, including SODs and catalase. Intriguingly, KEAP1 has been identified as a tumor suppressor in human cancers, illustrating that increased NRF2 activity or antioxidant response is protumorigenic in the setting of heightened metabolic rates and oxidative stress.

METABOLISM AND THE EPIGENOME

Cells have evolved a genome that mediates posttranscriptional and transcriptional mechanisms to import nutrients and harness energy and building blocks for the growing cell. In turn, metabolic intermediates generated from various nutrients can modulate gene expression, seemingly as an adaptive response to the metabolic milieu.^37,38,39 The epigenome is richly regulated by metabolic intermediates such as acetyl-CoA, S-adenosylmethionine (SAM), α-ketoglutarate, NAD+, and N-acetylglucosamine.⁴⁰ Acetyl-CoA mediates histone acetylation and modulates gene expression by rendering the genome accessible to specific transcriptional factors. SAM permits methylation of histones and DNA to prevent access of the transcriptional machinery to certain DNA sequences. α-Ketoglutarate serves as a cofactor for histone and DNA demethylation reactions, thereby countering the modifications provided by SAM. NAD+ serves as a cofactor for sirtuins that play a key role in histone deacetylation. N-acetylglucosamine, which is produced from glucose and glutamine, serves to modify histones. Other metabolic intermediates such as propionate, butyrate, formate, and crotonate also play a role in modifying histones, which have emerged as the metabolic sensor for gene expression.⁴⁰

The evolution of cancers is not only driven by hard-wired somatic DNA mutations and predisposing germline alleles but also by erasable covalent modifications of DNA and histones. A deregulated epigenetic regulatory system, which randomly silences or makes more accessible portions of the genome, could enhance the adaptability of cancer cells and thus provide a selection advantage that does not require DNA mutations. In this regard, deep sequencing of human cancers, particularly leukemias, has revealed that chromatin-modifying proteins, such as MLL2 (mixed-lineage leukemia protein 2), are frequently mutated at the somatic level.^41,42 Thus, somatic mutations in chromatin modifiers are surmised to increase the degrees of freedom for cancer cell adaptation to the dynamic tumor microenvironment and permit tumor progression.

HEMATOLOGIC NEOPLASMS AND METABOLISM

Normal hematopoietic stem cells (HSCs) and committed multipotent progenitor cells appear to have different metabolic programs, which may be adopted in the neoplastic state. The HSC resides in a hypoxic environment, and hence low mitochondrial mass and high glycolytic rates appear favored for survival. One of the mechanisms by which the hypoxic HSC niche induces stem cell quiescence is through HIF-1α and inhibits, which transactivates genes involved in glycolysis and inhibits DNA replication.³² Two studies of HSCs documented that HIF-1α is essential for the quiescent state, such that deletion of HIF-1α resulted in HSC proliferation and depletion of the HSC compartment.^43,44 Conversely, loss of VHL stabilized HIF-1α resulted in an expansion of the HSCs incapable of replenishing hematopoietic cells, resulting in cytopenia. Intriguingly, three studies showed that the Lkb1 tumor suppressor also plays a role in HSC quiescence; loss of Lkb1 resulted in cell proliferation and loss of the HSC compartment.^45,46,47 Interestingly, loss of Lkb1 in HSCs does not seem to be mediated solely through AMPK, as loss of AMPK in HSCs did not phenocopy the HSC nonquiescent phenotype seen with Lkb1 loss. Instead, one study identified the mitochondrial biogenesis coregulators, PGC1α and PGC1β, as being central to the Lkb1 loss phenotype.⁴⁵ Loss of Lkb1 in HSCs was associated with decreased expression of PGC1α and PGC1β and decreased mitochondrial DNA content and membrane potential. These studies collectively suggest that both HIF-1α and LKB1 are necessary for induction of quiescence by the hypoxic microenvironment. Loss of either HIF-1α or Lkb1 resulted in increased HSC proliferation and, presumably, commitment toward progenitors, thereby depleting the HSC pool. Although the hypoxic HSC microenvironment suggests that glycolysis predominates, it should be noted that hypoxic cells can still respire and consume oxygen. In fact, cytochrome c oxidase only ceases to function at oxygen tension well below 0.5 percent (as compared to the ambient 21 percent oxygen or approximately 6 percent oxygen found in perfused normal tissues). As such, the observation that loss of Lkb1 is associated with a mitochondriopathy in HSCs suggests that mitochondrial function is essential for HSC maintenance, and may resolve the paradox that HSCs seems to rely also on glutamine oxidation (Fig. 14–4).

The HSC uses symmetric commitment to replenish and maintain the stem cell pool and asymmetric division for the generation of committed progenitors (see Fig. 14–4). HIF-1α and Lkb1 appear to play a role in maintaining symmetric commitment. Fatty acid and glutamine oxidation, which requires mitochondrial function, may be required for asymmetric commitment toward progenitors. Surprisingly, despite anticipated HIF-mediated upregulation of glycolysis, the inducible glucose transporter GLUT1 is not highly expressed in HSCs and is only expressed upon differentiation.⁴⁸ Instead, the glutamine transporter ASCT2 (SLC1A5) is more highly expressed in HSCs, suggesting that glutamine oxidation via the TCA cycle unexpectedly plays a role in hypoxic stem cell metabolism. Consistent with the notion that hypoxic cells continue to respire, recent studies with human B cells or fibroblasts illustrate this capacity to oxidize glutamine in hypoxia when glucose is largely shunted away from the TCA cycle as lactate.^49,50 Interestingly, glutamine metabolism also appears to influence cell fate. For example, persistent glutamine metabolism in HSCs seems required for erythroid differentiation as glutamine deprivation blunts erythroid nucleotide synthesis and favors differentiation toward the myelomonocytic lineage even in the presence of erythropoietin.⁴⁸ Fatty acid oxidation, on the other hand, appears to be necessary for asymmetric division. Activation of peroxisome proliferator-activated receptor (PPAR)-δ, which augments mitochondrial function and fatty acid oxidation through the promyelocytic leukemia (PML)-PPARδ–fatty acid oxidation (FAO) pathway, increases asymmetric stem cell division, whereas inhibition of FAO enhances symmetric stem cell commitment.⁵¹ These findings suggest that mitochondrial oxidation of fatty acids and glutamine may play a role in asymmetric division and lineage commitment, while hypoxia-promoted glycolysis and, surprisingly, glutamine oxidation may be associated with the quiescent HSC pool. How these metabolic cues may affect cellular states through the epigenome is not yet known, however.

The history of the treatment of acute lymphocytic leukemia (ALL) underscores the importance of metabolism in our understanding of cancer. In fact, the first antimetabolite drug effective against any cancer, 4-aminopteroylglutamic acid (aminopterin), disrupts folate metabolism, which is intimately tied to NADPH production and nucleotide biosynthesis.⁵² The dependency of ALL on asparagine also provided a therapeutic opportunity through the use of l-asparaginase, which depletes plasma asparagine from patients.⁵³ The use of these antimetabolites led to the current state of therapy in which more than 90 percent of children with ALL achieve complete a substantial improvement from the uniformly lethal disease it presented as 60 years ago. Despite this remarkable clinical progress, our understanding of metabolism in acute leukemias is still rudimentary. However, advances in metabolomics and next-generation DNA sequencing have revealed new insights that provide additional texture to this understanding.

Leukemias have diverse oncogenic drivers, with many chromosomal translocations found in ALLs and some acute myelogenous leukemias (AMLs).^54,55 Whatever the oncogenic driver may be, the leukemic cells share common central metabolic pathways that support growth and replication, particularly glycolysis, glutaminolysis, and FAO (see Fig. 14–1). However, the fluxes through each of these pathways are likely different and dependent on the genomic alterations that are hardwired by mutations. Much of our current understanding comes from in vitro studies of leukemic cell lines that have revealed their high glycolytic rates and use of glutamine. Many early studies, including those of Otto Warburg, revealed that leukemic cells have very high rates of conversion of glucose to lactate.⁵⁶ Recent studies extend these observations; specifically, high glycolytic rates in primary and relapsed AML correlate with resistance to all trans-retinoic acid (ATRA). For these cases better overall survival and attainment of complete remission are achieved with induction chemotherapy.⁵⁷ Another study documents that primary childhood ALLs have gene expression profiles that suggest increased glycolysis and decreased oxidative phosphorylation and FAO.⁵⁸ Gene expression profiling also catalogued another link between glucose metabolism and leukemia with the discovery that MondoA expression is significantly elevated in ALL.⁵⁹ MondoA belongs to a family of transcription factors, including carbohydrate response element binding protein, which senses nutrient states and regulates metabolism.²³ MondoA was discovered as an extended family member of the MYC:Max network of transcription factors. MondoA dimerizes with Mlx (Max-like protein X) to bind target DNA sequences and regulate glucose metabolism. Thus ALL seems to depend on MondoA, with lowered MondoA expression in ALL reducing glycolytic metabolism and enhancing ALL cell differentiation.

Studies of AML cell lines in vitro also revealed their dependency on glutamine, which contributes in part to oxidation-reduction (redox) homeostasis through the generation of glutathione.^60,61 Primary AML cells, in contrast with normal CD34+ cells, depend on glutamine and undergo apoptosis with glutamine withdrawal.^62,63 Apoptosis appears to follow diminished mTORC1 activation. Furthermore, reduction of glutamine transport via ASCT2 (SLC1A5) diminishes AML cell line survival, underscoring the importance of glutamine metabolism in AML.⁶³ Clinical and laboratory experience with l-asparaginase also emphasizes the centrality of glutamine metabolism in ALL. l-Asparaginase is a highly effective agent against ALL, not only via the enzymatic activity embodied in its name, but also via “off-target” glutaminase activity.⁶³ Because glutamine also plays a critical role in the survival of ALL cells, they are likewise sensitive to l-asparaginase. The glutaminase activity of l-asparaginase additionally serves to reinforce the asparaginase activity of the drug, as glutamine released from the leukemic microenvironment can be used to regenerate asparagine in conjunction with aspartate via asparagine synthetase.⁵³ In one study, metabolites in the marrow of pediatric ALL were compared with those found in blood before and after standard therapy. Metabolites that were relatively depleted in the marrow prior to therapy include glutamine, glucose, and certain fatty acids.⁶⁴ These observations suggest that lymphoblasts or the microenvironment have heightened glycolysis, glutaminolysis, and perhaps fatty acid consumption. Upon therapy, there was severe depletion of asparagine and glutamine, with a more rapid recovery of peripheral glutamine levels after (therapy as also corroborated by another study).⁶⁵ Intriguingly, obese children with ALL do not respond well to l-asparaginase therapy, even with a significant reduction in asparagine and glutamine levels.⁶⁶ This phenomenon appears to be partly from the induction of glutamine synthetase in the marrow, which releases glutamine from adipocytes.⁶⁶ The notion that the tumor microenvironment, particularly mesenchymal cells, might contribute to the production of asparagine appears to be supported by the finding that marrow aspartate levels were higher than in the blood after l-asparaginase treatment while asparagine levels remained low. Thus, metabolism in the tumor microenvironment may affect therapeutic outcome.

Leukemic stem cells (LSCs) appear to adopt the ability of normal HSCs to use oxidative phosphorylation (see Fig. 14–4). Accumulating evidence suggests that FAO and ROS may also play important roles in LSC and HSC survival, self-renewal, and differentiation.^51,67 In one study, AML LSCs with high clonogenicity were isolated from stem cells with low ROS levels.⁶⁸ Gene expression analysis comparing these cells with leukemic cells with high ROS levels or with normal CD34+ HSCs revealed elevated expression of Bcl-2, which plays a role in mitochondrial metabolism, in addition to its canonical role in apoptosis.⁶⁹ The LSCs with high Bcl-2 expression appear to be metabolically quiescent as compared with normal CD34+ HSCs, demonstrating low oxygen consumption and lactate production. In contrast, ROS-high leukemic cells are more metabolically active and have lower colony-forming units. The ROS-low cells are dependent on oxidative phosphorylation and incapable of mounting a glycolytic response, as evidenced by inhibition of Bcl-2 resulting in diminished oxidative metabolism and decreased survival of the LSCs. By contrast, ROS-high leukemic and normal HSCs can mount a glycolytic response in response to Bcl-2 inhibition. In a separate study, inhibition of Bcl-2 with a small molecule in combination with the fatty oxidation inhibitor etomoxir resulted in a decrease in the AML LSC compartment,⁶⁸ suggesting that FAO may play a role in the survival of LSCs. If the AML LSCs are similar, at least in part, to normal HSCs, which use FAO for generation of progenitors, then the proliferation of AML cells from LSCs may require fatty acids. Collectively, these results suggest that LSCs may rely on oxidative phosphorylation and may use fatty acids as a source of fuel for survival and generation of more differentiated AML cells from the LSC pool. Use of FAO is expected to increase ROS, which seems to be required for myeloid differentiation from the HSC compartment. In this regard, induction of ROS, such as through the use of iron chelators, has been suggested as a therapeutic strategy that forces LSCs to differentiate.⁶⁷

Frequent mutations in AML, such as FLT3-ITD,^70,71 result in constitutive receptor tyrosine kinase activation, which culminates in activation of PI3K, as well as many downstream events that are associated with increased glycolysis and glutaminolysis (see Fig. 14–2). It is surmised that these pathways would increase the dependency of AML cells on metabolism and mitochondrial function. In this regard, AML cells are sensitive to inhibition of mitochondrial complex I with metformin.⁷² Intriguingly, a large study of 400 AML patients revealed a serum metabolic signature pointing to heightened glycolysis and TCA cycle activity in AML that is associated with resistance to cytosine arabinoside.⁷³ These observations led to a metabolic prognostic score based on the levels of six circulating metabolites. Although this study documents the alteration of metabolism in AML patients, the general applicability of the metabolic prognostic score remains to be determined.

The metabolic pathways (glycolysis, glutaminolysis, and FAO) associated with different leukemic states are surmised to support cellular function, but it could be speculated that these specific pathways are compatible with maintenance of the epigenome of that cellular state. Specifically, the concentrations (and fluxes) of specific metabolic intermediates (e.g., SAM, acetyl-CoA, and α-ketoglutarate) associated with specific metabolic states could modulate the epigenome. The epigenetic influence of metabolism is perhaps best illustrated by the discovery of germline mutations in key metabolic enzymes found in familial cancer syndromes and of somatic mutations of IDH1 and IDH2 in a variety of cancers, including AML and angioimmunoblastic lymphoma.⁴²

Somatic mutations of IDH were first discovered in gliomas through deep sequencing.⁷⁴ Whole-genome sequencing subsequently revealed the same in a karyotypically normal case of AML.⁷⁵ These findings bolstered the notion that hardwired mutations of metabolism could be tumorigenic. A breakthrough in our understanding of IDH mutations in hematologic neoplasm came from a landmark biochemical study of mutant IDH, which revealed a neomorphic activity of the mutant enzymes.⁷⁶ Instead of just being inactive, unable to convert isocitrate to α-ketoglutarate (Fig. 14–5), the mutant enzymes reduces α-ketoglutarate to form the oncometabolite 2-hydroxyglutarate (2-HG), which can be detected at high levels in AML.⁷⁷ The role of 2-HG in cell growth was illustrated by studies of the leukemic granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent TF1 cell line, which when deprived of GM-CSF displays diminished growth partially rescuable by exposure to 2-HG.^78,79 Biochemical studies of 2-HG indicate that it could compete with α-ketoglutarate in many oxygenase reactions that depend on α-ketoglutarate as a cofactor, specifically enzymes that are involved in DNA or histone demethylation.

The ability of 2-HG to interfere with epigenetic modifications suggests that IDH mutations promote tumorigenesis through the epigenome.³⁹ In this regard, genomics of AML reveal the mutual exclusivity of mutations of either IDH1 or IDH2 with mutations in TET2.⁴² TET2 produces a DNA demethylating enzyme and hence it appears that high levels of 2-HG production via IDH mutations phenocopies the loss of TET2 in AML. Furthermore, whole-genome methylation analysis uncovers distinct methylomes associated with IDH mutations, underscoring the role of IDH mutations in altering the epigenome in a way that makes myeloid progenitor cells permissive for leukemogenesis.⁸⁰ The emergence of specific drugs that inhibit IDH1 or IDH2 reveal that inhibition of mutant IDHs results in differentiation of AML cells. These observations indicate that the epigenome maintained by high levels of 2-HG prevents activation of a myeloid differentiation program, similar to the PML-RAR mutation found in acute PML, which can be induced to differentiate with retinoids. Intriguingly, IDH mutations are also found in other cancers, including angioimmunoblastic lymphomas, but not in other types of lymphomas.⁸¹

The lymphomas are a broad group of lymphoid malignancies spanning from the more indolent to the most aggressive forms, each with a spectrum of genomic alterations.^82,83,84,85 The majority of lymphomas evolve from B-cells at different stages of differentiation in the course of the germinal center reaction (Chap. 78). B-cells activated by T-cell–dependent antigens undergo rapid bursts of growth, forming germinal centers where somatic hypermutation occurs for generation of antibody diversity and plasmacytic differentiation. These phases of B-cell development demand high levels of bioenergetic support and are the stages from which lymphomagenesis is launched. Mantle cell lymphoma arises from the mantle zone. Burkitt lymphoma, emanating from MYC activation, emerges from the pregerminal center compartment. The germinal center type B-cell lymphoma arises from the germinal center compartment, and the activated B-cell (ABC) type of lymphoma develops from the plasmacytic stage. The lymphomas retain the high energetic demands of the precursor cells, and hence the aggressive lymphomas are staged and followed by fluorodeoxyglucose positron emission tomography (FDG-PET), which documents the high levels of glucose uptake and retention in these lymphomas.^86,87 It should be noted that the basis for high FDG-PET is the uptake and retention of 2-deoxyglucose through phosphorylation by HKs. A highly positive FDG-PET does not indicate whether glucose ends up being converted to lactate or being oxidized through the TCA cycle.

Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL) have high glycolytic flux driving glucose to lactate production. In clinically advanced cases, these lymphomas can present with severe lactic acidosis without any evidence of septicemia.^88,89 The high glycolytic flux is driven by MYC or PI3K activation of glycolysis in these lymphomas and by HIF-1α, which is stabilized in hypoxic regions of the lymphomas (see Fig. 14–2). High glycolytic flux renders models of lymphomas sensitive to glycolytic inhibitors as well as inhibitors of monocarboxylate transporters that export lactate.⁹⁰ Inhibition of these transporters and subsequent buildup of lactate result in the inability of lactate dehydrogenase to recycle NADH to NAD+, culminating in inhibition of glycolysis because GAPDH requires NAD+ for its function upstream in the glycolytic pathway. The inhibition of glycolysis causes lymphoma cells to rely further on oxidative phosphorylation, rendering them sensitive to the antidiabetic drug and mitochondrial complex I inhibitor, metformin.

Genetic alterations in lymphomas including B-cell receptor mutations and MYC activation link the genome to alterations in cell metabolism. B-cell receptor activating mutations increase PI3K signaling and render DLBCLs highly glycolytic.⁹¹ High glycolytic rates allow for the synthesis of ribose, glycine, and aspartate, which are building blocks for nucleotide biosynthesis (see Fig. 14–1). Glutamine is also essential for the production of nucleotides and fatty acids. In this regard, glutaminolysis is increased by oncogenic MYC in a model of human Burkitt lymphoma.^49,92,93,94 Hypoxic lymphoma cells increase glucose flux to lactate but continue to respire in a glutamine dependent fashion, such that inhibition of GLS with the small molecule BPTES diminishes lymphoma progression in preclinical xenograft models.⁴⁹

The rapid proliferation of aggressive lymphomas demands ample nucleotide pools for RNA and DNA synthesis. Many of the key nucleotide metabolic genes are direct targets of the MYC transcription factor, which plays a prominent role in many types of lymphomas.^95,96 Activation of normal lymphocytes results in a significant increase in 5-phosphoribosyl-pyrophosphate synthetase (PRPS). PRPS2 is not only a target of MYC essential for lymphomagenesis in transgenic mice, but its expression couples the regulation of protein synthesis with nucleotide synthesis.⁹⁷ Prps2 transcription is directly activated by MYC, and the 5′-untranslated region (UTR) of Prps2 requires the oncogenic translational factor eIF4E for its translation, thereby linking protein synthesis with the regulation of nucleotide metabolism. IMPDH1 and IMPDH2, which encode the inosine monophosphate dehydrogenases that catalyze the oxidation of inosine monophosphate to xanthosine monophosphate in nucleotide biosynthesis, are also MYC target genes. Increased expression of inosine monophosphate dehydrogenases (IMPDHs) is a feature of lymphomas, and IMPDH is also thought to play an additional role as a transcription factor.⁹⁸ Mycophenolic acid is an immunosuppressant that targets IMPDH in lymphocytes, but its role in the therapy of lymphomas is not well-studied. However, it is not only the size of the nucleotide pool that is lymphomagenic, but also the imbalanced nature of that pool. DNA replication fidelity relies on balanced pools of nucleotides, with deoxyguanosine triphosphate (dGTP) tending to be limiting amongst the deoxynucleoside triphosphates (dNTPs).^99,100 As such, the relative deficiency of deoxycytidine kinase in lymphomas could result in diminished deoxycytidine triphosphate (dCTP) pools that can induce replication stress and genomic instability.¹⁰¹ Alterations in nucleotide pools along with increased ROS production by mitochondria could then provide a mutator phenotype for the progression of lymphomas, which have relatively high mutational rates among cancers.

Polyamines play an important role in cell growth by providing polycations involved in DNA replication and dynamics. The synthesis of the polyamines, spermine and spermidine, starts with the synthesis of their precursor, putrescine, from ornithine catalyzed by ornithine decarboxylase (ODC), whose gene is one of the first recognized MYC targets.¹⁰² ODC is essential for transgenic murine lymphomagenesis and its activity could be inhibited by α-difluoromethylornithine (DFMO), which has not had a significant clinical impact despite being studied over the last several decades.¹⁰³ Spermidine is also involved as a cofactor in a unique posttranslational alteration of lysine to hypusine. Although this unusual amino acid is found in all eukaryotes, the only known protein containing hypusine is eukaryotic translation initiation factor eIF5A, which is required for lymphocyte activation.¹⁰⁴ Hypusinated eIF5A attenuates the translation of MYC, thereby providing a negative feedback loop, whose disruption accelerates MYC-mediated lymphomagenesis. The tumor-suppressive function of spermidine-dependent hypusinated eIF5A could underlie the reason why DFMO has not made a significant clinical impact.

Intriguingly, gene expression profiling also identified a group of DLBCL that displays high levels of expression of genes involved in oxidative phosphorylation, termed the OXPHOS group of DLBCL.¹⁰⁵ The OXPHOS group depends more on FAO for survival and growth as compared to the B-cell receptor group, which could also be defined by gene expression profiling. FAO requires functional peroxisomes or mitochondria.¹⁰⁶ Fatty acids longer than 12 carbons are conjugated with carnitine and then transported into peroxisomes or mitochondria via carnitine-palmitoyl transferase. Upon entry into the mitochondrial matrix, fatty acids are degraded into acetyl-CoA for further oxidation in the TCA cycle. In this regard, it is notable that MYC induces mitochondrial biogenesis in proliferating cells through activation of genes involve in the genesis and function of mitochondria.^19,107

In addition to FAO as a signature of a subset of DLBCL, alterations in lipid contents have also been documented. Using MYC-inducible models of lymphoma, glycerophosphoglycerol (PG) and cardiolipin (CL) were found to be elevated in a MYC-dependent manner.¹⁰⁸ Both PG and specifically CL are important for mitochondrial membrane integrity. These phospholipids are also elevated in human lymphomas with high MYC expression. On the other hand, phosphatidyl serine (PS), phosphatidyl inositol (PI), and the most abundant mammalian membrane phospholipid, phosphatidyl ethanolamine (PE), were decreased in these lymphomas. Intriguingly, ³¹P-MRS imaging has been used to determine the abundance of PE and phosphatidyl choline (PC) relative to nucleotide triphosphate (NTP) in DLBCL and has uncovered that poor clinical response to cyclophosphamide, hydroxydaunorubicin, methotrexate, and prednisone (CHOP)-based therapy correlates with a higher pretreatment ratio of phosphomonoesters to NTP levels.¹⁰⁹

The study of the OXPHOS subgroup of lymphomas also underscores observations that high aerobic glycolysis in lymphomas is not exclusive of OXPHOS, which relies on functional mitochondria that generate the majority of ATP.¹⁰⁵ The cell-of-origin (COO) classification of DLBCL into germinal center B-cell type (GCB) or ABC groups of lymphoma does not discretely segregate different metabolic features, although the ABC group tends to have higher expression of MYC. A significant fraction of DLBCL, however, has translocations or alterations in expression that increase Bcl-2 and MYC levels, resulting in a highly resistant group of “double-hit” DLBCL.¹¹⁰ The ability of MYC to induce metabolic rewiring and biomass accumulation (discussed above) and the effect of Bcl-2 on mitochondrial metabolism and apoptosis make this group of lymphomas particularly resistant to standard therapy.

Multiple myeloma is characteristically a MYC-driven cancer, particularly since MYC is overexpressed through spurious chromosomal rearrangements and MYC amplification.^111,112 In this regard, it is anticipated that heightened glycolysis and glutaminolysis play vital roles in myeloma development and progression. Although few studies have delineated the metabolic changes in myeloma, clinical FDG-PET scans are used to monitor disease response to therapy,¹¹³ suggesting that myeloma has increased glucose uptake and retention relative to neighboring normal marrow. Moreover, expression of the glucose transporters GLUT4, GLUT8, and GLUT11 are elevated in myeloma.¹¹⁴ The dependency of myeloma on glycolysis appears to sensitize myeloma cell lines to PDK1 inhibition, which diverts pyruvate away from lactate and into acetyl-CoA.¹¹⁵ These observations suggest that inhibition of glucose metabolism could potentiate response of myeloma to therapies.

It is notable that several studies showed significant inhibition of myeloma growth and survival with inhibition of NAD+ synthesis through nicotinamide phosphoribosyltransferase (NAMPT).¹¹⁶ The production of NAD+ is required for multiple metabolic processes, including glycolysis that depends on NAD+ for oxidation of glycolytic intermediates. In this regard, a preclinical model of B-cell neoplasia with plasmacytoid features displays sensitivity to a combination of NAMPT and lactate dehydrogenase A (LDHA) inhibition. The expression of NAMPT, which is a direct target of MYC, is elevated in myeloma.¹¹⁶ The NAMPT inhibitor, FK866, diminishes myeloma tumorigenesis, triggers autophagic cell death, and synergizes with proteasome inhibitors, which have significant clinical activity in multiple myeloma.¹¹⁷ Collectively, these studies suggest an important role of glucose metabolism in myeloma. However, relatively little is known currently about glutamine or fatty acid metabolism in this disease.

More than ninety years have passed since Otto Warburg first documented metabolic alterations in cancers, including the high rate conversion of glucose to lactate termed the Warburg effect or aerobic glycolysis. Much of our understanding of cancer metabolism has resulted from studies of solid tumors, which share many basic metabolic features with hematologic neoplasms. In particular, the central metabolic pathways of glycolysis and glutaminolysis seem to be similarly exploited by solid and hematologic neoplasm alike for cell growth, proliferation, and survival. Glucose and glutamine flux into cells provides for the production of ATP and building blocks for the growing cell. Furthermore, glutamine and glucose are also substrates for glutathione synthesis, which is vital for redox homeostasis of growing cells that produce ROS as metabolic byproducts. Resting cells, on the other hand, tend to rely on FAO, which provides the most efficient energy production. In this regard, evidence has emerged indicating that neoplastic stem cells also rely on FAO and, hence, could be targeted therapeutically via this route. Glucose, glutamine, and mitochondrial metabolism pathways offer similar inhibition strategies for proliferating hematologic neoplastic cells. One of the most remarkable therapeutic developments, however, is the discovery of IDH mutations in AML and lymphoma and the development of specific drugs targeting the mutant forms of IDH1 and IDH2. Furthermore, alterations of the AML methylome and the ability of mutant IDH inhibitors to induce differentiation of AML cells underscore the link between metabolites and the epigenome. It is through advances in our understanding of cancer metabolism that we have been able to develop therapies like these for mutant IDH, capitalize on the avidity of glucose uptake by hematologic neoplasms for diagnostic and followup FDG-PET scanning, and develop many more metabolic strategies that are hoped to provide new gains against these deadly malignancies.