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196 Part IV: Molecular and Cellular Hematology Chapter 14: Metabolism of Hematologic Neoplastic Cells 197

oxygen species (ROS) (Fig. 14–2). In this regard, various mechanisms provided by SAM. NAD+ serves as a cofactor for sirtuins that play a key
have evolved to eliminate these wastes that accumulate as cells dis- role in histone deacetylation. N-acetylglucosamine, which is produced
card entropy into the environment after consuming “negative entropy” from glucose and glutamine, serves to modify histones. Other meta-
(macromolecules) to survive and grow. Carbon dioxide and protons bolic intermediates such as propionate, butyrate, formate, and crotonate
are neutralized by carbonic anhydrase. Lactate is exported by mono- also play a role in modifying histones, which have emerged as the met-
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carboxylate transporters. Reactive oxygen species (ROS) are gener- abolic sensor for gene expression. 40
ated by the mitochondria and other cellular reaction pathways, such as The evolution of cancers is not only driven by hard-wired somatic
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via NADPH oxidases or disulfide bond formation. ROS participates DNA mutations and predisposing germline alleles but also by erasable
in signaling at ambient levels; however, very high levels of ROS result covalent modifications of DNA and histones. A deregulated epigenetic
in oxidative cellular stress. 34,35 In particular, electrons leaking from the regulatory system, which randomly silences or makes more accessible
mitochondrial electron transport chain (ETC) contribute to a large frac- portions of the genome, could enhance the adaptability of cancer cells
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tion of cellular ROS. Electrons are donated to the chain by NADH or and thus provide a selection advantage that does not require DNA
succinate at mitochondrial complexes I, II, and III, which all generate mutations. In this regard, deep sequencing of human cancers, particu-
ROS. Complexes I and II release ROS into the mitochondrial matrix, larly leukemias, has revealed that chromatin-modifying proteins, such
whereas complex III releases ROS into space on both sides of the inner as MLL2 (mixed-lineage leukemia protein 2), are frequently mutated
mitochondrial membrane. Complex I accepts electrons from NADH, at the somatic level. 41,42 Thus, somatic mutations in chromatin mod-
which is generated from TCA cycle oxidation, and passes them on to ifiers are surmised to increase the degrees of freedom for cancer cell
ubiquinone or coenzyme Q that also accepts electrons from succinate adaptation to the dynamic tumor microenvironment and permit tumor
via complex II (SDH). Coenzyme Q then passes electrons to complex progression.
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 HEMATOLOGIC NEOPLASMS AND
final electron acceptor. Upon accepting electrons at complexes I, III, and
IV, a proton is pumped into the intermembrane space, creating a proton METABOLISM
gradient across the inner mitochondrial membrane. The proton gradient Normal hematopoietic stem cells (HSCs) and committed multipotent
is dissipated through complex V or ATP synthase with the generation of progenitor cells appear to have different metabolic programs, which
ATP from ADP. During the process of making ATP, leakage of electrons may be adopted in the neoplastic state. The HSC resides in a hypoxic
from complexes I, II, and III generates superoxide from oxygen. environment, and hence low mitochondrial mass and high glycolytic
Superoxide is highly reactive and could damage membranes and rates appear favored for survival. One of the mechanisms by which the
proteins if unattenuated. Hence, superoxide dismutases (SODs) have hypoxic HSC niche induces stem cell quiescence is through HIF-1α and
evolved to convert superoxide to hydrogen peroxide, which is, in turn, inhibits, which transactivates genes involved in glycolysis and inhibits
neutralized by catalases and converted to water and oxygen. In addition DNA replication. Two studies of HSCs documented that HIF-1α is
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to enzymatic ROS neutralizers, the family of peroxiredoxins also plays essential for the quiescent state, such that deletion of HIF-1α resulted
an important role in titrating mitochondrial and cytosolic ROS by neu- in HSC proliferation and depletion of the HSC compartment. 43,44 Con-
tralizing hydrogen peroxide. Because oxidative stress imposed by ROS versely, loss of VHL stabilized HIF-1α resulted in an expansion of the
is a part of normal metabolism, a system of cellular response to this HSCs incapable of replenishing hematopoietic cells, resulting in cytope-
stress has evolved. Immediate response to ROS is mediated by SOD, nia. Intriguingly, three studies showed that the LKB1 tumor suppressor
catalase, peroxiredoxins, and glutathione. A sustained response to ROS also plays a role in HSC quiescence; loss of LKB1 resulted in cell pro-
is mediated chiefly through NRF2, which is a transcription factor that liferation and loss of the HSC compartment. 45–47 Interestingly, loss of
is negatively regulated by KEAP1, a protein that is directly inhibited by LKB1 in HSCs does not seem to be mediated solely through AMPK,
oxidative modification of sensitive cysteine residues. NRF2 activates as loss of AMPK in HSCs did not phenocopy the HSC nonquiescent
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many genes involved in redox homeostasis, including SODs and cata- phenotype seen with LKB1 loss. Instead, one study identified the mito-
lase. Intriguingly, KEAP1 has been identified as a tumor suppressor in chondrial biogenesis coregulators, PGC1α and PGC1β, as being central
human cancers, illustrating that increased NRF2 activity or antioxidant to the LKB1 loss phenotype. Loss of LKB1 in HSCs was associated
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response is protumorigenic in the setting of heightened metabolic rates with decreased expression of PGC1α and PGC1β and decreased mito-
and oxidative stress. chondrial DNA content and membrane potential. These studies collec-
tively suggest that both HIF-1α and LKB1 are necessary for induction
of quiescence by the hypoxic microenvironment. Loss of either HIF-1α
METABOLISM AND THE EPIGENOME or LKB1 resulted in increased HSC proliferation and, presumably, com-
Cells have evolved a genome that mediates posttranscriptional and mitment toward progenitors, thereby depleting the HSC pool. Although
transcriptional mechanisms to import nutrients and harness energy the hypoxic HSC microenvironment suggests that glycolysis predomi-
and building blocks for the growing cell. In turn, metabolic interme- nates, it should be noted that hypoxic cells can still respire and consume
diates generated from various nutrients can modulate gene expres- oxygen. In fact, cytochrome c oxidase only ceases to function at oxygen
sion, seemingly as an adaptive response to the metabolic milieu. 37–39 tension well below 0.5 percent (as compared to the ambient 21 percent
The epigenome is richly regulated by metabolic intermediates such as oxygen or approximately 6 percent oxygen found in perfused normal
acetyl-CoA, S-adenosylmethionine (SAM), α-ketoglutarate, NAD+, tissues). As such, the observation that loss of LKB1 is associated with
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and N-acetylglucosamine. Acetyl-CoA mediates histone acetylation a mitochondriopathy in HSCs suggests that mitochondrial function is
and modulates gene expression by rendering the genome accessible to essential for HSC maintenance, and may resolve the paradox that HSCs
specific transcriptional factors. SAM permits methylation of histones seems to rely also on glutamine oxidation (Fig. 14–4).
and DNA to prevent access of the transcriptional machinery to certain The HSC uses symmetric commitment to replenish and maintain
DNA sequences. α-Ketoglutarate serves as a cofactor for histone and the stem cell pool and asymmetric division for the generation of com-
DNA demethylation reactions, thereby countering the modifications mitted progenitors (see Fig. 14–4). HIF-1α and LKB1 appear to play a

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