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192 Part IV: Molecular and Cellular Hematology Chapter 14: Metabolism of Hematologic Neoplastic Cells 193

comprised of ribosomes. It is estimated that ribosomes constitute more
the brain. How whole organisms initiate autophagy (self-eating) during mark- than 50 percent of cellular dry mass, and hence ribosome biogenesis is
edly prolonged starvation has not been thoroughly studied. But autophagy is highly regulated and vitally important for cell growth and proliferation.
clearly necessary for mammalian development, particularly upon birth when Once a critical cell size (mass) is reached with a balanced nucleotide
deletion of specific autophagic regulators results in death. Although autoph- pool, DNA synthesis begins. Yeast cells sense nutrients, particularly
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agy plays an important role in mitochondrial and organellar homeostasis and glucose and glutamine, through pathways involving RAS and target of
cancer metabolism, it is discussed in Chap. 15; this chapter focuses primarily on rapamycin complex 1 (TORC1), which silence transcriptional repres-
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intermediary metabolism. sors of ribosome biogenesis. With nutrient deprivation, activation of
Although most of our cells are differentiated and do not proliferate, stem these transcriptional repressors provides a metabolic checkpoint that
restrains cells from growing in the absence of adequate bioenergetic
cell compartments are ubiquitous among tissues, allowing for replacement support. Hence, the normal feedback loops couple nutrient availability
of used or damaged cells. The hematopoietic stem cell and hematopoiesis with cell growth: no nutrients, no growth. The normal feedback loops
constitute probably the best-studied stem cell system. Cytokines, growth can be artificially disrupted by deletion of transcriptional repressors of
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factors, and the extracellular matrix provide the cues for stem cells to main- ribosomal biogenesis, rendering yeast mutants constitutively activated
tain their quiescent state or to awaken and differentiate to replenish lost for growth. These mutants resemble mammalian cancer cells, which
cells. In response to growth factors in the presence of nutrient-replete states, have mutations that drive autonomous cell growth with disregard for
stem cells self-renew, proliferate, and then differentiate. In nutrient-deprived nutrient availability. The severance of nutrient sensing from growth sig-
states, normal metabolic checkpoints forbid growth factor stimulated cells naling causes addiction of these yeast mutants to nutrients, such that
from proliferating. All of the mechanisms used by normal cells during fed and deprivation of glucose or glutamine results in nonviable mutants. Simi-
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starved states are potentially exploitable by neoplastic cells for their survival. larly, cancer cells are addicted to nutrients. 6
Cell growth in multicellular organisms requires additional cues in
Genetic mutations drive neoplastic cells to grow and proliferate regardless of addition to the availability of nutrients. Mammalian cells live in a com-
the availability of nutrients; in contrast, normal cells sense nutrients and do munity of cells and are constantly bathed in nutrients derived from the
not proliferate under starved conditions. In this chapter, basic cell metabolism circulation, but they do not proliferate unless there are appropriate cues
is covered along with discussions about growth signaling and its intersection from growth factors and the extracellular matrix. Mammalian cells can
with metabolism. Alterations in metabolism found in hematologic neoplastic be envisioned as bioreactors that require at least two signals to grow: (1)
cells are discussed in the context of therapeutic opportunities that are rapidly growth factor and (2) nutrients. Cell growth is arrested in the absence
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emerging from the latest basic research and translational efforts. 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. Indeed, the core metabolic pathways including glycolysis, glutami-
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CELL GROWTH AND METABOLISM nolysis, and the tricarboxylic acid (TCA) cycle link amino acid and glucose
metabolism to lipogenesis and nucleotide synthesis (Fig. 14–1). Glycolysis
HOMEOSTASIS starts with the transport of glucose into cells through several transporters,
The canonical cell has significant bioenergetic needs for maintenance known as GLUTs, with SLC2A1 (GLUT1) being one that is coupled with
and homeostasis. Protein synthesis and maintenance of cellular mem- cell growth stimulation. Once inside the cell, glucose is phosphorylated
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brane potentials consume most of the ATP produced under homeostatic in an ATP-consuming step by hexokinases (HK) with HKII being stimu-
conditions. In many differentiated or quiescent cells, it is believed that lated by many growth signals and directly regulated by the MYC oncogene
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fatty acid oxidation provides the bulk of the energy, followed by the use or the hypoxia inducible factor 1 alpha (HIF-1α). Glucose-6-phosphate
of glucose. In this regard, mitochondrial respiration is essential for adult (G6P) is used by the pentose phosphate pathway to produce ribose for
tissues and cells. It is notable, however, that specialized cell functions nucleotide synthesis (Fig. 14–1) or converted to fructose phosphate via an
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in the various organs could require different metabolic pathways. Glu- isomerization reaction catalyzed by glucose phosphate isomerase (GPI).
cocorticoid hormone-producing cells, for example, express specialized Fructose-6-phosphate is further phosphorylated with consumption of a
metabolic pathways. Although cardiac muscle cells depend heavily on second ATP through a rate-limiting step catalyzed by phosphofructoki-
fatty acid oxidation, skeletal muscle cells use glucose. The brain depends nase (PFK) to fructose-1,6-bisphosphate (F1,6BP). F1,6BP is converted
largely on glucose, but it can feed on ketone bodies under starved states. by aldolase and an isomerase to the three-carbon phosphorylated mol-
For differentiated cells, which are the bulk of cells in mammals, homeo- ecule, glyceraldehyde 3-phosphate (GAP), which is oxidized and phos-
stasis drives the demand for nutrients, to “the availability of which are phorylated using inorganic phosphate by the dehydrogenase, GAPDH,
determined by feeding and interorgan (liver, muscle, and endocrine tis- to 1,3-bisphosphoglycerate. The energy gained by nicotinamide adenine
sues) metabolic interplays. For example, lactate produced by exercising dinucleotide (NAD+)-mediated oxidation and phosphorylation is
muscle circulates back to the liver and is processed via the Cori cycle to released from 1,3-bisphosphoglycerate by phosphoglycerate kinase, which
produce glucose. Glucose plasma level is tightly controlled by the pan- transfers the high-energy phosphate bond to adenosine diphosphate
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creas, which produces insulin and glucagon, and by the liver (as well as (ADP) to form ATP. The resulting 3-phosphoglycerate (3-PG) provides a
kidney) that can produce glucose through gluconeogenesis. substrate for serine and glycine synthesis, for the production of glycerol,
or for the production of phosphoenol pyruvate (PEP) in glycolysis. Pyru-
CELL GROWTH: SIGNALING, NUTRIENTS, AND vate kinase mediates the transfer of the high-energy phosphate bond from
METABOLISM PEP to ADP producing ATP and pyruvate, which is the terminal substrate
of glycolysis. Collectively, glycolysis uses ATP to charge up several inter-
Normal cell growth and proliferation are triggered by extracellular cues. mediates for their transformations and uses NAD+ to oxidize intermedi-
Yeast cells, for example, only require the presence of nutrients to initi- ates and generate energy through new high-energy phosphate bonds with
ate cell growth or an increase in cell size. During this growth phase, inorganic phosphate. Each glucose molecule results in the production of a
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nutrients are imported and channeled into biomass, which is largely net two ATP molecules from ADP through glycolysis.

Kaushansky_chapter 14_p0191-0202.indd 192 17/09/15 6:35 pm