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198 Part IV: Molecular and Cellular Hematology Chapter 14: Metabolism of Hematologic Neoplastic Cells 199

cells, in contrast with normal CD34+ cells, depend on glutamine and ROS, such as through the use of iron chelators, has been suggested as a
undergo apoptosis with glutamine withdrawal. 62,63 Apoptosis appears to therapeutic strategy that forces LSCs to differentiate. 67
follow diminished mTORC1 activation. Furthermore, reduction of glu- Frequent mutations in AML, such as FLT3-ITD, 70,71 result in con-
tamine transport via ASCT2 (SLC1A5) diminishes AML cell line sur- stitutive receptor tyrosine kinase activation, which culminates in acti-
vival, underscoring the importance of glutamine metabolism in AML. vation of PI3K, as well as many downstream events that are associated
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Clinical and laboratory experience with l-asparaginase also emphasizes with increased glycolysis and glutaminolysis (see Fig. 14–2). It is sur-
the centrality of glutamine metabolism in ALL. l-Asparaginase is a mised that these pathways would increase the dependency of AML cells
highly effective agent against ALL, not only via the enzymatic activity on metabolism and mitochondrial function. In this regard, AML cells
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embodied in its name, but also via “off-target” glutaminase activity. are sensitive to inhibition of mitochondrial complex I with metformin.
Because glutamine also plays a critical role in the survival of ALL cells, Intriguingly, a large study of 400 AML patients revealed a serum meta-
they are likewise sensitive to l-asparaginase. The glutaminase activity of bolic signature pointing to heightened glycolysis and TCA cycle activ-
l-asparaginase additionally serves to reinforce the asparaginase activity ity in AML that is associated with resistance to cytosine arabinoside.
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of the drug, as glutamine released from the leukemic microenvironment These observations led to a metabolic prognostic score based on the
can be used to regenerate asparagine in conjunction with aspartate via levels of six circulating metabolites. Although this study documents the
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asparagine synthetase. In one study, metabolites in the marrow of alteration of metabolism in AML patients, the general applicability of
pediatric ALL were compared with those found in blood before and the metabolic prognostic score remains to be determined.
after standard therapy. Metabolites that were relatively depleted in the The metabolic pathways (glycolysis, glutaminolysis, and FAO)
marrow prior to therapy include glutamine, glucose, and certain fatty associated with different leukemic states are surmised to support cel-
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acids. These observations suggest that lymphoblasts or the microenvi- lular function, but it could be speculated that these specific pathways
ronment have heightened glycolysis, glutaminolysis, and perhaps fatty are compatible with maintenance of the epigenome of that cellular state.
acid consumption. Upon therapy, there was severe depletion of asparag- Specifically, the concentrations (and fluxes) of specific metabolic inter-
ine and glutamine, with a more rapid recovery of peripheral glutamine mediates (e.g., SAM, acetyl-CoA, and α-ketoglutarate) associated with
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levels after (therapy as also corroborated by another study). Intrigu- specific metabolic states could modulate the epigenome. The epigenetic
ingly, obese children with ALL do not respond well to l-asparaginase influence of metabolism is perhaps best illustrated by the discovery of
therapy, even with a significant reduction in asparagine and glutamine germline mutations in key metabolic enzymes found in familial cancer
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levels. This phenomenon appears to be partly from the induction of syndromes and of somatic mutations of IDH1 and IDH2 in a variety of
glutamine synthetase in the marrow, which releases glutamine from cancers, including AML and angioimmunoblastic lymphoma. 42
adipocytes. The notion that the tumor microenvironment, particularly Somatic mutations of IDH were first discovered in gliomas through
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mesenchymal cells, might contribute to the production of asparagine deep sequencing. Whole-genome sequencing subsequently revealed
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appears to be supported by the finding that marrow aspartate levels the same in a karyotypically normal case of AML. These findings bol-
were higher than in the blood after l-asparaginase treatment while stered the notion that hardwired mutations of metabolism could be
asparagine levels remained low. Thus, metabolism in the tumor micro- tumorigenic. A breakthrough in our understanding of IDH mutations
environment may affect therapeutic outcome. in hematologic neoplasm came from a landmark biochemical study
Leukemic stem cells (LSCs) appear to adopt the ability of normal of mutant IDH, which revealed a neomorphic activity of the mutant
HSCs to use oxidative phosphorylation (see Fig. 14–4). Accumulating enzymes. Instead of just being inactive, unable to convert isocitrate to
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evidence suggests that FAO and ROS may also play important roles α-ketoglutarate (Fig. 14–5), the mutant enzymes reduces α-ketogluta-
in LSC and HSC survival, self-renewal, and differentiation. 51,67 In one rate to form the oncometabolite 2-hydroxyglutarate (2-HG), which can
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study, AML LSCs with high clonogenicity were isolated from stem cells be detected at high levels in AML. The role of 2-HG in cell growth
with low ROS levels. Gene expression analysis comparing these cells was illustrated by studies of the leukemic granulocyte-macrophage
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with leukemic cells with high ROS levels or with normal CD34+ HSCs colony-stimulating factor (GM-CSF)-dependent TF1 cell line, which
revealed elevated expression of Bcl-2, which plays a role in mitochon- when deprived of GM-CSF displays diminished growth partially
drial metabolism, in addition to its canonical role in apoptosis. The rescuable by exposure to 2-HG. 78,79 Biochemical studies of 2-HG indi-
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LSCs with high Bcl-2 expression appear to be metabolically quiescent as cate that it could compete with α-ketoglutarate in many oxygenase reac-
compared with normal CD34+ HSCs, demonstrating low oxygen con- tions that depend on α-ketoglutarate as a cofactor, specifically enzymes
sumption and lactate production. In contrast, ROS-high leukemic cells that are involved in DNA or histone demethylation.
are more metabolically active and have lower colony-forming units. The The ability of 2-HG to interfere with epigenetic modifications sug-
ROS-low cells are dependent on oxidative phosphorylation and inca- gests that IDH mutations promote tumorigenesis through the epige-
pable of mounting a glycolytic response, as evidenced by inhibition of nome. In this regard, genomics of AML reveal the mutual exclusivity of
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Bcl-2 resulting in diminished oxidative metabolism and decreased sur- mutations of either IDH1 or IDH2 with mutations in TET2. TET2 pro-
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vival of the LSCs. By contrast, ROS-high leukemic and normal HSCs duces a DNA demethylating enzyme and hence it appears that high levels
can mount a glycolytic response in response to Bcl-2 inhibition. In a of 2-HG production via IDH mutations phenocopies the loss of TET2 in
separate study, inhibition of Bcl-2 with a small molecule in combination AML. Furthermore, whole-genome methylation analysis uncovers dis-
with the fatty oxidation inhibitor etomoxir resulted in a decrease in the tinct methylomes associated with IDH mutations, underscoring the role
AML LSC compartment, suggesting that FAO may play a role in the of IDH mutations in altering the epigenome in a way that makes mye-
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survival of LSCs. If the AML LSCs are similar, at least in part, to normal loid progenitor cells permissive for leukemogenesis. The emergence of
HSCs, which use FAO for generation of progenitors, then the prolif- specific drugs that inhibit IDH1 or IDH2 reveal that inhibition of mutant
eration of AML cells from LSCs may require fatty acids. Collectively, IDHs results in differentiation of AML cells. These observations indicate
these results suggest that LSCs may rely on oxidative phosphorylation that the epigenome maintained by high levels of 2-HG prevents activation
and may use fatty acids as a source of fuel for survival and generation of a myeloid differentiation program, similar to the PML-RAR mutation
of more differentiated AML cells from the LSC pool. Use of FAO is found in acute PML, which can be induced to differentiate with retinoids.
expected to increase ROS, which seems to be required for myeloid dif- Intriguingly, IDH mutations are also found in other cancers, including
ferentiation from the HSC compartment. In this regard, induction of angioimmunoblastic lymphomas, but not in other types of lymphomas. 81

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