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

Symmetric Division Asymmetric Division
High SLC1A5 (ASCT2; glutamine)
Low fatty acid oxidation
Low SLC2A1 (GLUT1; glucose)

Stem Cell
Stem Cell

Progenitor

High fatty acid oxidation
High SLC1A5
High GLUT1
High PPARδ

Figure 14–4. Metabolic features of hematopoietic stem cells undergoing symmetric and asymmetric division. Some of these features appear to be
preserved in leukemic stem cells.

role in maintaining symmetric commitment. Fatty acid and glutamine led to the current state of therapy in which more than 90 percent of
oxidation, which requires mitochondrial function, may be required children with ALL achieve complete a substantial improvement from
for asymmetric commitment toward progenitors. Surprisingly, despite the uniformly lethal disease it presented as 60 years ago. Despite this
anticipated HIF-mediated upregulation of glycolysis, the inducible glu- remarkable clinical progress, our understanding of metabolism in acute
cose transporter GLUT1 is not highly expressed in HSCs and is only leukemias is still rudimentary. However, advances in metabolomics and
expressed upon differentiation. Instead, the glutamine transporter next-generation DNA sequencing have revealed new insights that pro-
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ASCT2 (SLC1A5) is more highly expressed in HSCs, suggesting that vide additional texture to this understanding.
glutamine oxidation via the TCA cycle unexpectedly plays a role in Leukemias have diverse oncogenic drivers, with many chromoso-
hypoxic stem cell metabolism. Consistent with the notion that hypoxic mal translocations found in ALLs and some acute myelogenous leuke-
cells continue to respire, recent studies with human B cells or fibroblasts mias (AMLs). 54,55 Whatever the oncogenic driver may be, the leukemic
illustrate this capacity to oxidize glutamine in hypoxia when glucose cells share common central metabolic pathways that support growth
is largely shunted away from the TCA cycle as lactate. 49,50 Interestingly, and replication, particularly glycolysis, glutaminolysis, and FAO (see
glutamine metabolism also appears to influence cell fate. For example, Fig. 14–1). However, the fluxes through each of these pathways are
persistent glutamine metabolism in HSCs seems required for erythroid likely different and dependent on the genomic alterations that are hard-
differentiation as glutamine deprivation blunts erythroid nucleotide wired by mutations. Much of our current understanding comes from
synthesis and favors differentiation toward the myelomonocytic lineage in vitro studies of leukemic cell lines that have revealed their high gly-
even in the presence of erythropoietin. Fatty acid oxidation, on the colytic rates and use of glutamine. Many early studies, including those
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other hand, appears to be necessary for asymmetric division. Activa- of Otto Warburg, revealed that leukemic cells have very high rates of
tion of peroxisome proliferator-activated receptor (PPAR)-δ, which conversion of glucose to lactate. Recent studies extend these observa-
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augments mitochondrial function and fatty acid oxidation through tions; specifically, high glycolytic rates in primary and relapsed AML
the promyelocytic leukemia (PML)-PPARδ–fatty acid oxidation (FAO) correlate with resistance to all trans-retinoic acid (ATRA). For these
pathway, increases asymmetric stem cell division, whereas inhibition of cases better overall survival and attainment of complete remission are
FAO enhances symmetric stem cell commitment. These findings sug- achieved with induction chemotherapy. Another study documents
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gest that mitochondrial oxidation of fatty acids and glutamine may play that primary childhood ALLs have gene expression profiles that sug-
a role in asymmetric division and lineage commitment, while hypoxia- gest increased glycolysis and decreased oxidative phosphorylation and
promoted glycolysis and, surprisingly, glutamine oxidation may be FAO. Gene expression profiling also catalogued another link between
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associated with the quiescent HSC pool. How these metabolic cues may glucose metabolism and leukemia with the discovery that MondoA
affect cellular states through the epigenome is not yet known, however. expression is significantly elevated in ALL. MondoA belongs to a fam-
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ily of transcription factors, including carbohydrate response element
binding protein, which senses nutrient states and regulates metabo-
LEUKEMIAS lism. MondoA was discovered as an extended family member of the
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The history of the treatment of acute lymphocytic leukemia (ALL) MYC:Max network of transcription factors. MondoA dimerizes with
underscores the importance of metabolism in our understanding of Mlx (Max-like protein X) to bind target DNA sequences and regulate
cancer. In fact, the first antimetabolite drug effective against any cancer, glucose metabolism. Thus ALL seems to depend on MondoA, with low-
4-aminopteroylglutamic acid (aminopterin), disrupts folate metabolism, ered MondoA expression in ALL reducing glycolytic metabolism and
which is intimately tied to NADPH production and nucleotide biosyn- enhancing ALL cell differentiation.
thesis. The dependency of ALL on asparagine also provided a thera- Studies of AML cell lines in vitro also revealed their dependency
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peutic opportunity through the use of l-asparaginase, which depletes on glutamine, which contributes in part to oxidation-reduction (redox)
plasma asparagine from patients. The use of these antimetabolites homeostasis through the generation of glutathione. 60,61 Primary AML
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