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200 Part IV: Molecular and Cellular Hematology Chapter 14: Metabolism of Hematologic Neoplastic Cells 201

Activation of normal lymphocytes results in a significant increase in integrity. These phospholipids are also elevated in human lymphomas
5-phosphoribosyl-pyrophosphate synthetase (PRPS). PRPS2 is not only with high MYC expression. On the other hand, phosphatidyl serine (PS),
a target of MYC essential for lymphomagenesis in transgenic mice, but phosphatidyl inositol (PI), and the most abundant mammalian mem-
its expression couples the regulation of protein synthesis with nucleo- brane phospholipid, phosphatidyl ethanolamine (PE), were decreased
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tide synthesis. Prps2 transcription is directly activated by MYC, and in these lymphomas. Intriguingly, P-MRS imaging has been used to
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the 5′-untranslated region (UTR) of Prps2 requires the oncogenic trans- determine the abundance of PE and phosphatidyl choline (PC) relative
lational factor eIF4E for its translation, thereby linking protein synthesis to nucleotide triphosphate (NTP) in DLBCL and has uncovered that
with the regulation of nucleotide metabolism. IMPDH1 and IMPDH2, poor clinical response to cyclophosphamide, hydroxydaunorubicin,
which encode the inosine monophosphate dehydrogenases that catalyze methotrexate, and prednisone (CHOP)-based therapy correlates with a
the oxidation of inosine monophosphate to xanthosine monophosphate higher pretreatment ratio of phosphomonoesters to NTP levels. 109
in nucleotide biosynthesis, are also MYC target genes. Increased expres- The study of the OXPHOS subgroup of lymphomas also under-
sion of inosine monophosphate dehydrogenases (IMPDHs) is a feature scores observations that high aerobic glycolysis in lymphomas is not
of lymphomas, and IMPDH is also thought to play an additional role exclusive of OXPHOS, which relies on functional mitochondria that
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as a transcription factor. Mycophenolic acid is an immunosuppres- generate the majority of ATP. The cell-of-origin (COO) classification
sant that targets IMPDH in lymphocytes, but its role in the therapy of of DLBCL into germinal center B-cell type (GCB) or ABC groups of
lymphomas is not well-studied. However, it is not only the size of the lymphoma does not discretely segregate different metabolic features,
nucleotide pool that is lymphomagenic, but also the imbalanced nature although the ABC group tends to have higher expression of MYC. A sig-
of that pool. DNA replication fidelity relies on balanced pools of nucleo- nificant fraction of DLBCL, however, has translocations or alterations
tides, with deoxyguanosine triphosphate (dGTP) tending to be limiting in expression that increase Bcl-2 and MYC levels, resulting in a highly
amongst the deoxynucleoside triphosphates (dNTPs). 99,100 As such, the resistant group of “double-hit” DLBCL. The ability of MYC to induce
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relative deficiency of deoxycytidine kinase in lymphomas could result in metabolic rewiring and biomass accumulation (discussed above) and
diminished deoxycytidine triphosphate (dCTP) pools that can induce the effect of Bcl-2 on mitochondrial metabolism and apoptosis make
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replication stress and genomic instability. Alterations in nucleotide this group of lymphomas particularly resistant to standard therapy.
pools along with increased ROS production by mitochondria could
then provide a mutator phenotype for the progression of lymphomas, MYELOMAS
which have relatively high mutational rates among cancers.
Polyamines play an important role in cell growth by providing Multiple myeloma is characteristically a MYC-driven cancer, particu-
polycations involved in DNA replication and dynamics. The synthesis larly since MYC is overexpressed through spurious chromosomal rear-
of the polyamines, spermine and spermidine, starts with the synthe- rangements and MYC amplification. 111,112 In this regard, it is anticipated
sis of their precursor, putrescine, from ornithine catalyzed by ornithine that heightened glycolysis and glutaminolysis play vital roles in mye-
decarboxylase (ODC), whose gene is one of the first recognized MYC loma development and progression. Although few studies have delin-
targets. ODC is essential for transgenic murine lymphomagenesis and eated the metabolic changes in myeloma, clinical FDG-PET scans are
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its activity could be inhibited by α-difluoromethylornithine (DFMO), used to monitor disease response to therapy, suggesting that myeloma
which has not had a significant clinical impact despite being studied has increased glucose uptake and retention relative to neighboring nor-
over the last several decades. Spermidine is also involved as a cofactor mal marrow. Moreover, expression of the glucose transporters GLUT4,
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in a unique posttranslational alteration of lysine to hypusine. Although GLUT8, and GLUT11 are elevated in myeloma. The dependency of
this unusual amino acid is found in all eukaryotes, the only known myeloma on glycolysis appears to sensitize myeloma cell lines to PDK1
protein containing hypusine is eukaryotic translation initiation factor inhibition, which diverts pyruvate away from lactate and into acetyl-
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eIF5A, which is required for lymphocyte activation. Hypusinated CoA. These observations suggest that inhibition of glucose metabo-
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eIF5A attenuates the translation of MYC, thereby providing a negative lism could potentiate response of myeloma to therapies.
feedback loop, whose disruption accelerates MYC-mediated lympho- It is notable that several studies showed significant inhibition
magenesis. The tumor-suppressive function of spermidine-dependent of myeloma growth and survival with inhibition of NAD+ synthesis
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hypusinated eIF5A could underlie the reason why DFMO has not made through nicotinamide phosphoribosyltransferase (NAMPT). The
a significant clinical impact. production of NAD+ is required for multiple metabolic processes,
Intriguingly, gene expression profiling also identified a group of including glycolysis that depends on NAD+ for oxidation of glycolytic
DLBCL that displays high levels of expression of genes involved in intermediates. In this regard, a preclinical model of B-cell neoplasia with
oxidative phosphorylation, termed the OXPHOS group of DLBCL. plasmacytoid features displays sensitivity to a combination of NAMPT
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The OXPHOS group depends more on FAO for survival and growth and lactate dehydrogenase A (LDHA) inhibition. The expression of
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as compared to the B-cell receptor group, which could also be defined NAMPT, which is a direct target of MYC, is elevated in myeloma. The
by gene expression profiling. FAO requires functional peroxisomes or NAMPT inhibitor, FK866, diminishes myeloma tumorigenesis, triggers
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mitochondria. Fatty acids longer than 12 carbons are conjugated with autophagic cell death, and synergizes with proteasome inhibitors, which
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carnitine and then transported into peroxisomes or mitochondria via have significant clinical activity in multiple myeloma. Collectively,
carnitine-palmitoyl transferase. Upon entry into the mitochondrial these studies suggest an important role of glucose metabolism in mye-
matrix, fatty acids are degraded into acetyl-CoA for further oxidation loma. However, relatively little is known currently about glutamine or
in the TCA cycle. In this regard, it is notable that MYC induces mito- fatty acid metabolism in this disease.
chondrial biogenesis in proliferating cells through activation of genes More than ninety years have passed since Otto Warburg first docu-
involve in the genesis and function of mitochondria. 19,107 mented metabolic alterations in cancers, including the high rate conver-
In addition to FAO as a signature of a subset of DLBCL, alterations sion of glucose to lactate termed the Warburg effect or aerobic glycolysis.
in lipid contents have also been documented. Using MYC-inducible Much of our understanding of cancer metabolism has resulted from
models of lymphoma, glycerophosphoglycerol (PG) and cardiolipin studies of solid tumors, which share many basic metabolic features with
(CL) were found to be elevated in a MYC-dependent manner. Both hematologic neoplasms. In particular, the central metabolic pathways
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PG and specifically CL are important for mitochondrial membrane of glycolysis and glutaminolysis seem to be similarly exploited by solid

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