Received: 31 May 2018 Revised: 24 August 2018 Accepted: 10 September 2018

DOI: 10.1002/cnr2.1139

REVIEW

Metabolic underpinnings of leukemia pathology and treatment

Travis Nemkov | Angelo D'Alessandro | Julie A. Reisz

Department of Biochemistry and Molecular

Genetics, University of Colorado Anschutz Abstract
Medical Campus, Aurora, CO, USA
Background: Carcinogenic transformation of white blood cells during hematopoie-
Correspondence
Julie A. Reisz, Department of Biochemistry
sis leads to the development of leukemia, a cancer characterized by incompetent
and Molecular Genetics, University of immune cells and a disruption of normal bone marrow function. Leukemias are diverse
Colorado Anschutz Medical Campus, 12801 E.
17th Ave., MS 8101, Aurora, CO 80045, USA.
in type, affected population, prognosis, and treatment regimen, yet a common theme
Email: [email protected] in leukemia is the dysregulated metabolism of leukemic cells and leukemic stem cells
Funding information with respect to their noncancerous counterparts.
US National Institutes of Health, Grant/Award
Numbers: T32 HL007171 and NIH T32 Recent findings: In this review, we highlight current findings that elucidate meta-
HL007171; Boettcher Webb‐Waring, Grant/
bolic traits unique to the four major types of leukemia, which confer carcinogenic sur-
Award Number: Biomedical Research Award
vival but can be potentially exploited for therapeutic intervention. These metabolic
features can work in conjunction with or be independent of unique aspects of the
bone marrow microenvironment that can also influence cell survival and proliferation,
thus sustaining carcinogenesis.
Conclusion: Deepening our understanding of the interactions of leukemias with
their niche environments in vivo will inform future treatments for leukemia, particu-
larly for those that are refractive to tyrosine kinase inhibitors and other therapeutic
mainstays.

KEY W ORDS

metabolism, leukemia, mass spectrometry, metabolomics, stable isotope tracing, tumor

microenvironment

1 | I N T RO D U CT I O N The second classification, acute vs chronic leukemia, refers to the

degree of cell maturity prior to carcinogenic transformation. Acute
Leukemias are a group of hematological malignancies caused by the leukemias are malignancies of immature hematopoietic cells, and in
rapid production of abnormal white blood cells. Such atypical white contrast, chronic leukemias are characterized by the transformation
blood cells are not functional immune cells and, through space occu- of partially matured hematopoietic cells. In general, chronic leukemia
pied, ultimately impair the ability of the bone marrow to produce suf- progresses more slowly than acute cases, the latter of which, if left
ficient numbers of red blood cells, platelets, and normal white blood untreated, can result in death within weeks.
cells. Several classifications exist to characterize the four major types The ongoing search for effective strategies to treat hematological
of leukemia, each of which involves the oncogenic transformation of cancers is not unlike other cancers in that a precise and thorough
progenitor cells that are biased toward specific fates in the hematopoi- understanding of their distinct genotypic and metabolic states, espe-
etic hierarchy. Lymphocytic leukemia refers to the transformation of cially in comparison to their normal counterparts, can provide targets
marrow progenitor cells that become lymphocytes, including natural for selective, robust, and lasting cytoreduction of cancer cells. Investi-
killer, T, and B cells. In myelogenous (or myeloid) leukemia, malignant gations of hematopoiesis, particularly in the context of leukemia
transformation occurs in the marrow progenitor cells that mature into development, face several substantial challenges. First, although isola-
the cells of the myeloid lineage, which includes monocytes, mast cells, tion of the specific progenitor populations is possible using flow
basophils, neutrophils, eosinophils, erythrocytes, and thrombocytes. cytometry, cell numbers are often low as the populations are small.

Cancer Reports. 2018;e1139. wileyonlinelibrary.com/journal/cnr2 © 2018 Wiley Periodicals, Inc. 1 of 13

https://doi.org/10.1002/cnr2.1139
2 of 13 NEMKOV ET AL.

A second major challenge is heterogeneity among tumors of the same However, while valuable, these approaches are sharply limited by
leukemia type resulting from unique tumor niches, genetic variability the breadth of information obtained in comparison to NMR and, in
among humans, comorbidities, and as yet unidentified disease‐related particular, MS experiments. This review will focus on recent investiga-
or disease‐causing mutations. The advent of systems biology‐based tions of metabolism in the context of leukemia that serve as major
approaches such as omics technologies (genomics, transcriptomics, efforts to identify mechanisms of drug resistance, biological phenom-
proteomics, metabolomics, among others) has transformed this ena underlying relapse, and new targets for leukemia therapy.
research by generating complex datasets that provide a unique view Hematopoiesis begins at the stage of hematopoietic stem cells
into disease pathology and thus enable the development of novel (HSCs), which are largely quiescent and maintain a self‐renewing
therapies. Of the different tiers in the central dogma, metabolism capacity. HSCs reside in the bone marrow, an organ marked by hyp-
represents that which is closest to the cellular phenotype and oxia and metabolic regulation by HIF‐1α.4 As a result, HSC homeosta-
1-3
most responsive to environmental stimuli. As such, metabolomics sis relies primarily on anaerobic glycolysis,5 fatty acid metabolism,6
(ie, the study of small molecules <1500 Da) has emerged as the mitophagy, and autophagy7 with little contribution of oxidative
approach most amenable for detecting rapid, dynamic changes in phosphorylation and high antioxidant defense systems, thus
cellular state that are biologically impactful but not manifested at the protecting this limited and precious cell population against the
genome level due to timing or magnitude of change. adverse effects of reactive oxygen species (ROS) and reactive nitrogen
Techniques for performing wide‐scale metabolomic analyses rely species (RNS). Once activated, HSCs progress into multipotent
on nuclear magnetic resonance (NMR) spectroscopy or mass spec- progenitor cells (MPPs), a population devoid of self‐renewal and
trometry (MS) that provide direct readouts of complex metabolite marked by robust proliferation (Figure 1). Through sophisticated
mixtures and quantify changes occurring in response to stimuli, drug molecular signaling that is only partially elucidated at current day,
treatment, time, disease, and so on. In contrast, alternative approaches MPP subtypes (ie, MPP2, MPP3, and MPP4) are molecularly biased
to measure single or several metabolites include autofluorescence, towards committing to specific lineages; MPP2 cells primarily form
multiphoton, hyperspectral, and fluorescence lifetime imaging micros- granulocyte/macrophage progenitors (GMP) and megakaryocyte‐
copy (FLIM), as well as commercial kits that spectrophotometrically erythroid progenitors (MEP), while MPP3 cells predominantly fuel
quantify individual metabolites based on a surrogate reading of exog- GMP production and MPP4 cells for lymphoid lineage progenitors,
enously added enzyme activities. Extracellular flux (XF) analyzers can both via common myeloid progenitors (CMPs), or common lymphoid
provide more holistic views of dynamic metabolism by determining progenitors (CLPs, also known as MPP4).8 Key modulators of hemato-
extracellular acidification rate (ie, glycolytic flux) and oxygen consump- poiesis include inflammation,9,10 the HSC microenvironment, mito-
tion rate (ie, mitochondrial metabolism). These alternative approaches chondrial dynamics,11 reactive oxygen species,12 and epigenetics,13
are utilized widely and are included in studies discussed herein. among other factors.

FIGURE 1 Overview of hematopoiesis and transformation. Hematopoietic stem cells (HSCs) possess self‐renewing capacity and are maintained
as a small population. Generation of multipluripotent progenitor (MPP) cells devoid of self‐renewal, but with active proliferation, marks the path
toward differentiation to ultimately form the cellular components of blood. Carcinogenic transformation at the HSC stage generates leukemic
stem cells (LSCs); transformation of mature or immature cells at points downstream generates leukemic cells. Shown here is an overview of
metabolic features of the leukemia types. Abbreviations: ATP, adenosine triphosphate; CE, cholesterol ester; CoQ10, coenzyme Q10; FA, fatty
acid; FAA, fatty acid amide; GLS, glutaminase; GSH, reduced glutathione; HIF‐1α, hypoxia‐inducible factor 1α; NAD, nicotinamide adenine
dinucleotide; PC, phosphatidylcholine; PGF2α, prostaglandin F2α; PPP, pentose phosphate pathway; R‐2HG, (R)‐2‐hydroxyglutarate; RNS, reactive
nitrogen species; ROS, reactive oxygen species; SM, sphingomyelin; TG, triglyceride; TxB3, thromboxane B3
NEMKOV ET AL. 3 of 13

Carcinogenic transformation of HSCs generates leukemic stem constitutive hypoxia‐inducible factor 1α (HIF‐1α) expression, and most
cells (LSCs, Figure 1), which are characterized by their impaired capac- critically widespread and continuous interactions with the stroma that
ity for differentiation, enhanced proliferation, and unlimited self‐ function to regulate metabolic and redox homeostasis in these cells.
renewal.14 These cells are central components of disease progression, A mass spectrometry‐based metabolomic study of B lymphocytes
as well as drug resistance and relapse. Contradictory to long‐term from CLL patients (n = 4) in comparison to healthy controls (n = 5)
HSCs, LSCs are more dependent on oxidative respiration and have revealed alterations in glutaminolysis in B‐CLL cells, specifically
upregulated antioxidant defense systems, both adaptations which decreased levels of glutamine and glutamate and increased alanine, a
poise this cell population for rapid proliferative capacities. In addition product of glutaminolysis (Figure 2A).19 Further evidence supporting
to arising from the LSC pool,15 leukemic cells also initiate at more dysregulated glutaminolysis was found in accompanying proteomic
mature developmental stages; we discuss next the four leukemia experiments which revealed increased levels of glutaminase and gluta-
subtypes and how their unique metabolic features underlie current mine synthetase in CLL cells.19 In comparison to normal lymphocytes,
treatment approaches and provide cues for the development of CLL cells have a dysregulated cell growth cycle and are primed for
therapies in the future. A prominent and common feature of leukemia hypoxic response by constitutive low level expression of HIF‐1α20
cell biology is the cellular interaction with the tumor microenviron- even in normoxic environments such as circulating blood. Transcript‐
ment. The stroma proves to be a key regulator of cell metabolism level expression of HIF‐1α is variable among CLL patients21 and has
and redox state in a manner that controls transformation and prolifer- been correlated to unfavorable prognoses in a study of 88 CLL
ation. The various roles of the tumor microenvironment are noted patients.22 HIF‐1α has also been implicated as a key regulator of the
within each of the leukemia subtypes, but additionally, this topic is interactions between CLL cells and the stroma. This molecular inter-
also addressed on a larger scale in the concluding section with a facing of CLL cells with their dynamic microenvironment confers CLL
particular focus on extracellular matrix protein dynamics. plasticity, dynamically regulating their metabolism and cell cycle. Stud-
ies of the interaction between CLL cells and the stroma often utilize
coculturing of patient CLL cells with stromal cell lines. For example,
2 | C HR O NI C LY M P H O C Y T I C L E U K E M I A a 2‐hour coculturing of patient CLL cells with NK Tert and other

Chronic lymphocyc leukemia (CLL) results from an overproduction of

abnormal B cell lymphocytes by the bone marrow. CLL is a slow‐
progressing disease but unfortunately does not have a cure. Approxi-
mately 20 000 new cases of CLL will be diagnosed in the United
States in 2018, equating to 1.2% of all newly diagnosed cancers, and
5‐year survival rates were measured at 84% from 2008 to 2014
(seer.cancer.gov, Table 1). Cells associated with CLL are often quies-
cent and are found in bone marrow, lymph nodes, the spleen, and
circulating blood. The diverse microenvironments in which CLL cells
reside require them to be highly adaptive to oxygenation status and
molecular signals originating in the stroma. For example, cell signaling
in non‐CLL cells in lymph nodes regulates CLL cell proliferation there
as opposed to at other sites.16 Additionally, the microenvironment in FIGURE 2 Metabolic alterations observed in CLL cells. A, Flux
the bone marrow of CLL patients is characterized by increased expres- through glutaminolysis is increased as evidenced by decreased Gln
sion at the mRNA and protein level of the BCL‐2 family of proteins, and Glu, elevated ala, and increased expression of glutaminase and
crucial antiapoptotic factors that sustain CLL without affecting prolif- glutamine synthetase. Coculturing with stroma increases TCA cycle
activity in CLL cells. B‐CLL cells have lower levels of cystine and the
eration17 (and references therein). Eluding apoptosis is a hallmark of
xCT cystine transporter; experimental evidence suggests that the
CLL cells and underlies their propensity for chemoresistance, thus
stroma can regulate CLL redox homeostasis by reducing the cystine
serving as a promising target for therapy.18 Metabolically, CLL cells disulfide to cysteine, which enters cells and is utilized for glutathione
are characterized by—among other features—altered glutaminolysis, biosynthesis

TABLE 1 Statistics of leukemia incidence and survival in the United States

CLL CML AML ALL ALL—Pediatric
a
Est. new cases in 2018 20,000 8430 19,520 5970 3000a
Percentage of cancers diag. in 2018 1.2% 0.5% 1.1% 0.4% 0.2%
5‐year survival rate 84% 67.6% 27.4% 71% (All)a; 40% (Adult)b 85%‐90%c

Statistics obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program (seer.cancer.gov) unless otherwise noted.
a
American Society for Clinical Oncology (cancer.net).
b
Goldstone et al. Blood. 2008, 111, 1827.
c
Pui et al. Leukemia. 2014, 28, 2336.
4 of 13 NEMKOV ET AL.

stromal cell lines increased oxygen consumption rate and maximum newly diagnosed cancers (seer.cancer.gov). CML is rare in children
respiratory capacity and reduced glucose uptake relative to CLL cells and has a 5‐year survival rate of 67.6% in the United States (seer.can-
alone.17 Several mitochondrial features in CLL cells were unaffected cer.gov, Table 1). CML is marked by a translocation between chromo-
by coculturing, including levels of reactive oxygen species (ROS), outer somes 9 and 22, termed the Philadelphia chromosome, which results
mitochondrial membrane potential, mtDNA copy number, and expres- in the genetic fusion of the BCR and ABL genes, leading to the expres-
sion levels of proteins involved in oxidative phosphorylation.17 In addi- sion of cytosolic Bcr‐Abl kinase. Bcr‐Abl is a constitutively active tyro-
tion, glycolytic flux, as judged by extracellular acidification rate (ECAR), sine kinase whose presence leads to sustained activation of signaling
was unaltered by coculturing with NK Tert cells for 2 or 24 hours.17 involving the MAPK,27 JAK/STAT,28 MYC, RAS,29 and PI3K30 axes
Mass spectrometry‐based metabolomics revealed that coculturing (reviewed in Cilloni and Saglio31). In addition, Bcr‐Abl increases the
+
increased NAD along with levels of metabolites involved in the tricar- rate of cell proliferation and interferes with cell cycle signaling and
boxylic acid (TCA) cycle, gluconeogenesis, and de novo synthesis of quality control mechanisms, particularly those involved in DNA repair,
nucleotides. Furthermore, levels of nucleotide triphosphates in CLL allowing for rapid growth and propagation of mutations.32
cells were elevated at later time points such as at 24 and 48 hours Treatments for CML often utilize tyrosine kinase inhibitors (TKIs)
of coculturing.17 Taken together, these results help to elucidate the to target the Abl kinase ATP‐binding domain, and although they are
manners by which the stroma regulates the energy demands of CLL largely successful at inducing a remission state, TKIs are not curative
cells and reveals that such effects are evident as quickly as 2 hours fol- for CML. Commonly used TKI therapies for CML include imatinib mes-
lowing initial interaction of these cell types. Longer term coculturing ylate (marketed as Gleevec) and subsequent generation drugs nilotinib
has been performed using patient CLL cells cocultured with stromal and dasatinib. The second‐generation drugs provide faster responses
cell line HS‐5 for 6 days and revealed instead increased glucose and are more potent but do not affect the overall survival rate for
uptake and expression of GLUT3 along with elevated glycolytic activ- CML patients compared to first‐generation imatinib.33 Third‐genera-
ity, as judged by increases in the expression of glycolytic enzymes, tion drug ponatinib provides a treatment option for CML patients with
ATP levels, and ECAR relative to CLL cells alone.23 the T315I mutation of Bcr‐Abl,34 but very likely, there are other muta-
Redox homeostasis and metabolism are crucial in CLL cells, which tions and other molecular mechanisms not yet identified that contrib-
possess higher basal levels of reactive oxygen species (ROS) than nor- ute to inefficacy in TKI compounds. Resistance to TKI therapy is a
24
mal lymphocytes, thus rendering these cells more susceptible to oxi- significant challenge in treatment of the disease; thus, it is crucial to
dative stressors. Recent findings revealed that the synthesis of understand the full picture of Bcr‐Abl's far‐reaching effects in order
glutathione (GSH), a key tripeptide antioxidant, in CLL cells is regu- to better target future treatments.
lated by cells in the bone marrow stroma. Coculturing did not affect Bcr‐Abl increases glucose transport and renders CML cells more
protein‐level expression of a rate‐limiting enzyme of GSH synthesis, glycolytic than their normal counterparts,35 promoting the Warburg
and additional experiments revealed that CLL cells have reduced cys- effect that is commonly seen in many cancers. Imatinib has been
tine content and lower expression of the xCT cystine transporter com- shown to decrease flux through glycolysis through both reduction in
pared to normal lymphocytes (Figure 2B).25 It was found in this study glucose uptake and inactivation of glycolytic enzymes.36,37 In one
that the stroma reduces cystine to cysteine which is then taken up by study, a continuous exposure of K562, an erythroleukemia CML cell
CLL cells for GSH synthesis, revealing a mechanism by which the line, to imatinib lead to inhibition of glycolysis and induction of
stroma regulates the redox environment of CLL cells.25 The reliance autophagy by mechanisms involving activation of AMPK and suppres-
of CLL cells and other cancer cells on extracellular import of cyste- sion of S6K1.38
ine/cystine to sustain GSH synthesis has been exploited as a treat- In addition to investigations of glycolysis, several studies have
ment option for these cancers. An engineered form of human aimed to develop a more comprehensive cellular context for how
cysteinase with two activating point mutations was recently shown CML cells differ metabolically from their healthy counterparts and to
to deplete the extracellular cysteine/cystine pool and kill CLL cells which degree the various TKI treatments recapitulate the phenotype
26
from patients and a mouse model. Cysteinase treatment reduced of noncancerous cells. In one such study, the plasma of newly diag-
tumor size in breast and prostate cancer xenografts and prolonged nosed CML patients before and after TKI treatment was compared
(doubled) survival in a mouse model of CLL.26 Lastly, in patient cells to the plasma of age‐matched healthy control patients using gas chro-
and mouse splenocytes, a treatment of 0.1 μM cysteinase significantly matography‐mass spectrometry‐based metabolomics.39 A comparison
reduced intracellular GSH and increased superoxide levels, disrupting of newly diagnosed patient (prior to TKI exposure, n = 26) plasma to
intracellular redox homeostasis in a manner sufficient to induce cell the plasma of healthy controls (n = 26) revealed nine metabolites sig-
death.26 nificantly altered: lactate, isoleucine, glycine, glucose, galactose, and
myo‐inositol elevated in CML; glycerol, myristate, and sorbitol
decreased.39 TKI therapy recipients were classified using clinical
3 | C HR O NI C M YE L O I D LE U K E M I A criteria as being resistant (n = 26) or sensitive (n = 26) to therapy.39
In the plasma of these patients, myristate and glycerol emerged as
Chronic myeloid leukemia (CML), also known as chronic myelogenous potential biomarkers for TKI responsiveness, both elevated in the
leukemia, is a cancer caused by transformed and growth‐unrestricted sensitive CML group.
myeloid cells (Figure 1). In the United States this year, an estimated In a wider metabolomic approach, leukocytes and plasma of CML
8430 new cases of CML will be diagnosed, corresponding to 0.5% of patients were obtained at the time of diagnosis, following hydroxyurea
NEMKOV ET AL. 5 of 13

(HU) treatment (a common first cytoreductive step), and following

subsequent TKI treatment using imatinib, nilotinib, or dasatinib.40
Principal component analysis (PCA) revealed a clustering of newly
diagnosed patients with the samples obtained following HU treat-
ment. This group was separated from a clustering of patient samples
following TKI to healthy control samples, suggesting a metabolic
rewiring induced by TKIs that render the cells more phenotypically
similar to non‐CML leukocytes. The PCA trend existed in the patient
plasma as well but was more evident in the leukocytes. A prominent
theme of the findings in this study is that measurable metabolic dis-
ruptions that occur in the newly diagnosed patients in comparison to FIGURE 3 Metabolic alterations observed in CD‐34+ CML cells:
healthy controls are normalized, though not necessarily fully, by TKI Increased fatty acid oxidation leads to elevated levels of
treatment.40 For example, such conclusions were observed for hexose acylcarnitines and increased enrichment of TCA cycle metabolites and
amino acids from stable isotope labeled palmitate. TCA flux is also
phosphate content in cells (increased in CML), hexose content in
increased via the enhanced activity of anaplerotic enzyme pyruvate
plasma (low in CML), decreased late glycolysis intermediate phospho-
carboxylase
glycerate (decreased in CML), and leukocyte and plasma amino acid
levels (increased and decreased, respectively, in CML).40 In a compar- the observed increases in anaplerosis and oxidative metabolism in
ison of the three TKIs used, samples from dasatinib‐treated patients CD‐34+ CML cells are in fact a unique phenotype and are not
were found to cluster apart from the other TKIs, perhaps reflective reproducible in control CD‐34+ cells absent of CML.45 Such thorough
of the known higher incidence this drug has for off‐target effects. studies of the fine details involved in how CML reprograms cell
Resistance to imatinib and other TKIs, which occurs in a minority metabolism, both in stem and differentiated cells, are crucial to
of patients, is believed to be a consequence of other mutations in the identify new avenues for selective and efficacious treatments,
Abl domain that affect drug binding. As a result, alternative therapies particularly for patients that are insensitive to TKI therapy.
for CML continue to be explored. One such effort, reported earlier this
year, utilizes ivermectin, an antiparasitic compound. Ivermectin
induces autophagy in breast cancer tumors by interfering with the 4 | ACUTE MYELOID LEUKEMIA
mTOR/Akt pathway,41,42 and has been shown to induce cell death in
AML cells via chloride‐dependent membrane hyperpolarization and Acute myeloid leukemia (AML) is a hematological cancer that develops
43
increased ROS. This study compared CML cell line K562 to primary specifically in the myeloid lineage of the hematopoietic cellular
CML cells and normal bone marrow cells, the latter two both CD‐34+ hierarchy and results in the accumulation of immature myeloblasts
(ie, expressing a cell surface marker indicating stemness) and found that have a blockade in downstream cellular differentiation. An esti-
that ivermectin induced caspase‐dependent apoptosis in CML but mated nearly 20 000 patients were diagnosed in 2017 (seer.cancer.
not normal hematopoietc cells via mitochondrial dysfunction and gov, Table 1). While great strides have been made during the last half
oxidative stress.44 Molecular signaling propagated by kinases in the century to treat AML thus improving survival rates, it remains an
AKT/mTOR pathway was reduced following ivermectin treatment, aggressive malignancy with poor prognoses of less than 30% 5‐year
and increases in levels of superoxide and total intracellular ROS were relative survival rates for all patients (seer.cancer.gov). While
both observed. Additionally, ivermectin was found to synergize with outcomes are much better for patients younger than 60 years with
TKIs nilotinib and dasatinib to increase the amount of CML apopto- cure rates near 35% to 40%, prognoses for patients over the age of
sis.44 TKIs efficiently target differentiated cells, allowing leukemic 60 are particularly poor in which only 5% to 15% of patients are in
stem cells to persist, thus further motivating the development of remission.46 These poor prognostic rates arise due to lack of response,
innovative treatment approaches for CML. A recent study utilized or high rate of relapse, to the initial therapy.47
MS‐based metabolomics to profile CD‐34+ cells versus CD‐34− AML is heterogeneous and classified principally by cytological and
(differentiated) cells from four CML patients.45 CD‐34+ cells were genetic characteristics. While patient blood smear assessments and
marked by increased fatty acid oxidation (FAO) as illustrated by characterization of cell‐specific markers by flow cytometry have been
decreased levels of free fatty acids, increased acylcarnitine content, historically used to diagnose AML, the advent and continuous innova-
and increased utilization of [U‐13C] palmitate into the TCA cycle and tion of gene and transcript sequencing technologies has expanded
amino acids (Figure 3).45 In addition, decreased lactate levels in CD‐ classification of molecular genetic subgroups.48 An analysis of 200
34+ cells suggested a greater fraction of pyruvate carbons being AML patient genomes enabled the functional categorization of several
13
utilized in the TCA cycle. Indeed, [U‐ C] glucose tracing revealed that mutations thus detailing how multivariate data can be organized and
although no changes were observed in pyruvate dehydrogenase potentially translated into new therapeutic strategies.49 These catego-
(responsible for pyruvate decarboxylation and the formation of ace- ries include impaired cell signaling, chromosomal dynamics, epigenetic
tyl‐CoA), the activity of anaplerotic enzyme pyruvate carboxylase homeostasis, and deregulation of both the transcription and splicing
(conversion of pyruvate to oxaloacetate) was increased in CD‐34+ processes. Given the dense connectivity of biological networks, it is
CML cells.45 Further experiments utilized CD‐34+ cells from control not surprising that the deregulated processes identified on the genetic
(non‐CML) patients to confirm via palmitate and glucose tracing that tier also have significant metabolic components.
6 of 13 NEMKOV ET AL.

Metabolomic approaches have been successfully applied to eluci-

date metabolic programs of AML cells both basally and in response to
drug treatments, as well as provide diagnostic and prognostic bio-
markers (Figure 1 for summary). Wang and colleagues applied NMR
to characterize features in 183 patients with AML compared to 232
age‐matched and gender‐matched healthy controls to identify a num-
ber of distinct metabolic features of disease.50 This study detailed
distinct metabolic pathways pertinent to energy metabolism including
glycolysis, TCA cycle, amino acid (AA), and fatty acid (FA) metabolism.
The steady‐state levels of these compounds were also able to
distinguish between various disease burdens, highlighting the value
of metabolomics as an analytical readout. Additional work expanded
on these findings with the use of GC‐MS and provided preliminary
evidence that lipid levels can also potentially be used to distinguish
between leukemia subtypes.51,52 FAs are released from membrane
lipids by lipases, then conjugated first to CoA by acyl‐CoA ligases,
and then to carnitine by carnitine palmitoyltransferase 1 (CPT1) at FIGURE 4 Metabolic features of AML cells. A, Mutant isocitrate
the outer membrane of the mitochondria. Upon transport into the dehydrogenase (IDH) generates oncometabolite (R)‐2‐
hydroxyglutarate from a‐ketoglutarate. B, Hallmarks of drug‐resistant
mitochondria, they undergo FAO and generate acetyl‐CoA to fuel
AML cells include a reliance on glutamine to fuel glutathione (GSH)
the TCA cycle. Interestingly, the FA transporter CD36 has been
biosynthesis and pyrimidine synthesis. Additionally, drug‐resistant
suggested as a prognostic marker in AML.53 A unique population of cells have elevated pentose phosphate pathway (PPP) activity
CD36+ leukemic stem cells (LSCs) identified in murine gonadal adi- particularly of rate‐limiting enzyme glucose 6‐phosphate
pose tissue was reliant on FAO and was similar to both CD36+ CML dehydrogenase (G6PDH)
and AML cells in humans.54 In addition, coculture of AML blasts and
bone marrow adipocytes increased lipolysis‐FA transport axis that precursor cells, poising them for leukemic transformation.66-68 Given
55
was abrogated with inhibition of CPT1A. These metabolic adapta- the active role IDH mutations play in leukemic development and
tions protected LSCs from chemotherapy54 and are also exploited in progression, a number of small molecule inhibitors of IDH have been
additional models of AML drug resistance.56 Furthermore, AML cell developed and are currently being tested or have already received
populations that are not enriched for LSCs but are drug resistant, such FDA approval (more extensively reviewed in Ragon and DiNardo69).
as those resistant to cytarabine, also upregulate CD36, fatty acid oxi- In addition, 2HG can alone be used as a prognostic marker in AML
dation, and overall mitochondrial activity.57 Taken together, these patients positive for IDH1/2 mutations,50 or in combination with the
studies highlight a central role for mitochondria in AML development abundance of pyruvate, lactate, αKG, and glycerol‐3‐phosphate to
and drug resistance, further supported by the finding that inhibiting predict survival outcomes.70 The implementation of high‐throughput
mitochondrial translation can serve as a therapeutic strategy in metabolomic technologies in the future will enable the rapid screening
treating AML.58 of patient samples71,72 and expand upon the utility of metabolomics in
Molecular subtype can also directly contribute to metabolic pro- clinical biochemistry.73
grams in AML. One such category of mutations seen in roughly 20% Another common set of mutations that predict for poor outcome
of AML occurs in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2, occur in signaling genes including activating mutations caused by
which represent the cytosolic and mitochondrial isoforms, respec- internal tandem duplications (ITD) in FMS‐like tyrosine kinase 3
tively). These NADP(+)‐dependent enzyme isoforms catalyze the oxi- (FLT3).74 This mutation has become a sought‐after target in the treat-
dative decarboxylation of isocitrate to produce α‐ketoglutarate (αKG) ment of AML due to the successful development and implementation
and CO2 and play integral roles in the TCA cycle as well as the of TK inhibitors. While inhibition of FLT3 has proven effective in
maintenance of cytosolic redox homeostasis, among other functions. treating AML,75,76 short‐lived remission rates have prompted subse-
Mutations in these genes result in the dysregulation of cell mainte- quent research into possible cellular adaptive mechanisms and have
nance and proliferation, and ultimately contribute to tumorigenesis pointed to significant metabolic contributions. Studies into the down-
in large part due to a gain of function that enables IDH to convert stream effects of FLT3 inhibition have determined that these cells are
αKG into (R)‐2‐hydroxyglutarate (R‐2HG),59,60 the enantiomer of (S)‐ acutely susceptible to oxidative stress, particularly due to accumula-
2HG produced by lactate dehydrogenase or malate dehydrogenase tion of mitochondrial reactive oxygen species that induce apoptosis.77
under hypoxic or low pH conditions (Figure 4A).61-63 Classified as a As revealed by synthetic lethal shRNA screening in combination with
central oncometabolite, R‐2HG is a competitive inhibitor of αKG‐ FLT3 inhibition, drug‐resistant cells can upregulate the activity of
dependent dioxygenases such as ten‐eleven translocation 2 protein ataxia telangiectasia mutated (ATM) and its downstream target
(TET2), which converts 5‐methylcytosine to 5‐hydroxymethylcytosine glucose 6‐phosphate dehydrogenase (G6PD) to activate the pentose
64
in the process of DNA methylation (reviewed in Parker and Metallo phosphate pathway, thus enabling the cells to maintain reduced
and Sciacovelli and Frezza65). Accumulation of R‐2HG can thus glutathione at levels sufficient to cope with oxidative stress.77 Indeed,
destabilize the epigenetic and metabolic landscape of hematopoietic AML cells depend strongly upon glutathione metabolism78,79 and
NEMKOV ET AL. 7 of 13

glutaminolysis to generate glutamate for glutathione synthesis Within the context of longer term treatment strategies, nearly all
(Figure 4B).80,81 Glutamine utilization may also be required for pediatric and adult cases of ALL are treated with methotrexate (MTX).
pyrimidine synthesis, which represents an additional target for MTX is a potent inhibitor of dihydrofolate reductase, an indispensable
AML.82 Taken together, these studies have defined a viable therapeu- folate pathway enzyme required to generate folate cofactors for the
tic strategy to eliminate drug‐resistant cells by targeting FLT3 signal- synthesis of nucleotides and S‐adenosylmethionine. Thus, MTX
ing in combination with glutamine metabolism and redox balance to confers cytotoxicity by interfering with nucleic acid synthesis along
treat AML (Gregory bioRxiv 2018).83 with other molecular mechanisms. MTX is utilized in a variety of
cancer types; however, adverse effects are common, and can include
acute kidney injury,97 cognitive/memory impairment,98 leuko-
5 | A C U T E LY M P H O B L A S T I C L E U K E M I A encephalopathy,99 and myelopathy. As MTX is the subject of at least
hundreds of clinical trials, we will highlight here only several of the
Acute lymphoblastic leukemia (ALL) results from the transformation of most recent developments regarding its role in the treatment of ALL
hematopoietic B cell or T cell progenitors. ALL is the most common with a particular focus on multiple metabolic manipulations used in
pediatric cancer, accounting for 80% of childhood leukemias.84 conjunction.
Adult‐onset ALL is most prevalent in white males age >70 years First, a CRISPR‐Cas9 screen of the HEL (erythroblast‐like) cell line
(seer.cancer.gov, Table 1). For pediatric B‐ALL, the remission rate is identified formimidoyltransferase cyclodeaminase (FTCD) as being
95% with 5‐year survival in the range of 85% to 90%.85 For adults, linked to MTX sensitivity.100 FTCD is a crucial enzyme in the histidine
remission is achieved in 85% of patients but 5‐year survival is only degradation pathway, which utilizes tetrahydrofolate. Depletion of
~40%86 and decreases to 7% if a relapse occurs.87 Independent of genes in this pathway decreased MTX sensitivity—in particular,
age, relapsed ALL is associated with poor survival rates. Known CRISPR‐Cas9‐induced knockdown of FTCD in CML cells reduced both
genetic alterations, including mutations, fusions, deletions, and flux through the histidine catabolic pathway and MTX sensitivity.100
other modifications, are associated with 50% of adult and ~70% of Accordingly, His supplementation was hypothesized to increase MTX
pediatric ALL cases.88 ALL is a heterogeneous disease marked by sensitivity by further disrupting the folate pathway. As anticipated,
reprogrammed metabolism and atypical molecular signaling and, like tumors grown in mice treated with HEL cells were decreased in size
CML, can be induced by the presence of the Philadelphia chromosome upon combination treatment of MTX + His vs either agent alone;
and expression of Bcr‐Abl, particularly in adult patients. We will focus importantly, no adverse effects on other organs were observed up to
here on the most recent investigations of ALL cell metabolism as 15 days.100 Histidine supplementation thus provides an intriguing
fuller pictures of ALL subtypes are recently and individually reviewed potential route for facile dietary enhancement of MTX for leukemias.
89,90 91-93
(B‐ALL ; T‐ALL ). A separate study investigated the effects of MTX when used in
All cases of pediatric ALL, along with many adolescent, young conjunction with mTOR inhibitors for the treatment of B‐ALL.
adult, and adult cases, are treated with asparaginase (ASNase) therapy Elevated mTOR activity is associated with poor prognoses in B‐ALL
as a frontline approach to cytoreduction. It has been known for a half cases, but the effects of mTOR inhibitors when used alongside de
century that asparagine (Asn), normally a nonessential amino acid, is novo DNA synthesis inhibitors like MTX or 6‐mercaptopurine (6‐MP)
essential to ALL cells due to deficient activity of asparagine synthe- were not clear. Here, Ph+ B‐ALL cell lines BV173 and SUP‐B15 were
tase.94
A sharp reduction of the cellular Asn pool using ASNase, which treated for 48 hours with MTX (30 nM) or 6‐MP (10 μM) in the
hydrolyzes the Asn amide to generate aspartate and ammonia, presence of mTORC inhibitors MLN0128 (100 nM) or rapamycin
sufficiently retards mRNA translation to ultimately induce apoptosis (10 nM).101 In all cases, mTORC inhibitors protected the cells from
95
in ALL cells. Unfortunately, although ALL cells are particularly reliant killing via MTX or 6‐MP.101 Interestingly, TKI inhibitor dasatinib
on Asn, cross‐reactivity of ASNase with other cell types results in also protected cells from the effects of MTX via decreased mTOR
significant side effects to an extent that has limited the use of ASNase signaling.101 From a mechanistic viewpoint, inhibition of mTORC1,
in adult ALL cases. To rectify the off‐target effects, other sources and known to slow cell proliferation, is believed to render cells less
preparations of ASNase are under investigation. For example, a recent sensitive to MTX and other agents that interfere with DNA/RNA
study compared retrospectively the standard of care Escherichia coli synthesis and quality control.101
enzyme with a polyethylene glycol conjugated (PEGylated) version in Returning to the unique features of ALL metabolism, another
96
122 ALL patients over age 14. Major findings included a prolonged approach to ALL treatment utilizes glucocorticoids such as dexameth-
half‐life of the PEGylated form, a 2‐month increase in relapse‐free sur- asone and prednisolone to inhibit cell proliferation by impeding
vival time (~11 vs ~9 months with the non‐PEG‐conjugated enzyme) glycolysis, upon which ALL cells are highly reliant to produce ATP
in patients under age 35, but no change in outcomes measured by and NAD+. In general, glucocorticoids interfere with glycolysis by
96
metrics such as remission rate and survival time. The occurrence mechanisms such as blocking glucose uptake and reducing the expres-
and the intensity of side effects measured (such as liver and kidney sion of glycolytic enzymes like pyruvate kinase; however, these drugs
damage) were also comparable between the two ASNase forms.96 are not sufficient to induce remission when used alone. Cancer cells
Resistance to ASNase therapy can occur through several mechanisms; exposed to glucocorticoids rewire away from glycolysis toward mito-
from a metabolic standpoint, glutamine/glutamate metabolism has chondrial metabolism and processes like autophagy in order to meet
attracted attention as these can also serve as precursors for Asn (see energetic demands for growth and proliferation and thus become
Marini et al95 for a recent review on asparaginase therapy in ALL). more sensitive to drugs that target these aspects of cell metabolism.
8 of 13 NEMKOV ET AL.

One such recent study profiled CCRF‐CEM clones exposed to

dexamethasone alone or in combination with etoposide, an inhibitor
of topoisomerase 2102 that disrupts mitochondrial homeostasis,103
and other anticancer drugs. Three phenotypic subtypes emerged: (1)
cells that were resistant to dexamethasone independent of etoposide
treatment, (2) cells where an additive effect was observed (termed
CEM‐ADD), (3) cells responsive to dexamethasone but with no
observed synergy in the presence of etoposide (termed CEM‐
NON).104 Reduced glycolysis was measured in both CEM‐ADD and
CEM‐NON, as judged by decreased lactate levels, decreased mRNA
expression of glycolytic genes hexokinase 2 (HK2) and lactate dehy-
drogenase A (LDHA), and decreased protein expression of HK2.104
CEM‐ADD cells exposed to dexamethasone for 48 hours followed
by treatment for 72 hours with oligomycin, an inhibitor of ATP
synthase, died in greater numbers than untreated cells and cells
exposed to either agent alone. FIGURE 5 Glucose metabolism in ALL cells. Gatekeeper
transcription factors PAX5 and IKZF1 limit ATP production through
In a separate study, the effects of antibiotic tigecycline were
glycolysis to prevent transformation. Together, genetic lesions and
investigated for cytotoxicity against ALL cells. Using pediatric ALL cell Bcr‐Abl rewire metabolism to allow for rapid glycolytic flux. PP2A is
lines,3 primary ALL CD34+ progenitors and lymphocytes, normal bone required by ALL cells and activates the PPP to sustain redox
marrow CD34+ cells, and peripheral blood mononuclear cells (PBMCs), homeostasis alongside rapid proliferation
a synergistic effect of tigecycline with doxorubin and (separately)
vincristine was identified.105 In the CCRF‐CEM cell line, primary ALL effective for B‐lymphoid ALL but not in myeloid leukemias, was
34+ progenitors, and primary ALL lymphocytes, mitochondrial respira- linked to glucose metabolism via the NR3C1 protein, which is
tion was adversely impacted by 2 hours following treatment with increased 6‐fold to 20‐fold in B‐lymphoid cells vs myeloid leukemia
tigecycline alone. Glycolysis increased up to 6 hours, perhaps as com- cells.106 NR3C1 is positively regulated by IKZF1 and PAX5, and
pensation, but sharply decreased thereafter (final time point at several experiments revealed that modulation of the levels of these
24 hours). All levels of tigecycline tested (5‐20 μM) for the three cell transcription factors correlated with the response to glucocorticoid
populations resulted in decreased ATP levels (luminescence assay), prednisolone.106
increased ROS (DCF assay/flow cytometry), increased content of In a subsequent report, serine/threonine phosphatase 2A (PP2A)
oxidized DNA (8‐hydroxyguanine by ELISA), and increased protein was revealed to be essential to B cell tumors with a primary function
oxidation (protein carbonyl content by ELISA).105 Interestingly, no of shifting glucose metabolism from glycolysis to the PPP to generate
difference was observed in mitochondrial membrane potential at reducing equivalents (ie, NADPH) that counteract oxidative stress
baseline when comparing the primary ALL CD34+ progenitors, ALL (Figure 5).107 Normal B cells possess low PPP activity due to
lymphocytes, normal bone marrow CD34+ progenitors, and PBMCs; the repressed expression of PPP enzymes by PAX5 and IKZF1
however, in these experiments, the primary ALL cells were found to (Figure 5).107 Loss of PP2A in B cell leukemic cells increased glucose
have greater mitochondrial mass, reserve respiratory capacity, and utilization and glycolysis products ATP and lactate; such changes were
ATP. Finally, a xenograft mouse model (CCRF‐CEM cells) found that not observed in myeloid leukemic cells, and mitochondrial metabolism
the combinations of tigecycline with vincristine and (separately) with was unchanged in both cell types.107 Deletion of PP2A in B‐lymphoid
doxorubicin were most effective in limiting tumor size within the cells decreased flux through the PPP, which also was not observed in
range of the 14 days tested. myeloid cells. The PP2A deletion was found to increase phosphoryla-
Muschen and colleagues have recently reported new insights into tion of 6‐phosphofructokinase/fructose 2,6‐bisphosphatase 2 (Pfkfb2)
the regulation of glucose metabolism in normal and malignant B cells, at Ser483, enhancing its kinase activity (at the expense of its
particularly in contrast to malignant myeloid cells. In one such study, phosphatase activity), thereby promoting glycolysis over the PPP and
the transcription factors PAX5 and IKZF1, which regulate genes illustrating a critical metabolic switch regulated by PP2A.107 The
involved in glucose uptake and metabolism, were identified as limiting effects of this deletion were reversed by overexpression of fructose
ATP production via glycolysis and metabolite flow into the TCA cycle 2,6‐bisphosphate phosphatase 2 TIGAR in B‐ALL cells lacking PP2A,
in manners that protect against transformation.106 Lesions in the as judged by the restoration of NADPH/NADP ratios. Overall, these
PAX5 and IKZF1 genes and/or altered expression are found in the and accompanying findings identify a unique reliance of malignant B
majority of adult and pediatric B‐ALL cases, leading to a loss of cells on the PPP and thus define a vulnerable metabolic pathway for
gatekeeper functionality that results in enhanced glucose metabolism therapeutic intervention.107
and ATP generation (Figure 5). To illustrate, the introduction of Activation of protooncogene MYC is well documented for various
Bcr‐Abl in mice with wild‐type PAX5 did not alter glucose uptake cancers and, through transcriptional regulation, increases metabolic
or utilization (as judged by ATP generation), but in mice activity through glycolysis and glutaminolysis (reviewed in Hsieh
haploinsufficient for PAX5, Bcr‐Abl increased glucose uptake 50‐fold et al108). Notch signaling upregulates MYC, and consequently the
106
and ATP levels 25‐fold. The response to glucocorticoids, which are PI3K/Akt pathway,109 and approximately half of T‐ALL patients
NEMKOV ET AL. 9 of 13

possess activating mutations in NOTCH1.110 Recently, in the context yet unknown genetic mutations associated with the disease etiology
of ALL, resistance to γ‐secretase inhibitors (GSIs), used to impede and/or impacting treatment response.
Notch signaling, was found to be associated with the loss of tumor
suppressor PTEN.111 Treatment of PTEN+/+ ALL mice with GSI DBZ
revealed using MS‐based metabolomics increases of glucose and its 6 | CO NC LUSIO N— TU MOR
downstream metabolites, both in glycolysis and the PPP, in compari- M I C RO E N V I R O N M E N T
son to untreated PTEN+/+ ALL mice, and DBZ treated and untreated
PTEN−/− ALL mice.111 Leukemic mice lacking PTEN had higher lactate The role of the microenvironment in harboring and promoting the
levels and a restored glucose metabolic phenotype (in comparison to growth and development of leukemic cells is becoming an increasingly
PTEN+/+ untreated) independent of DBZ exposure. Growth and appreciated aspect of hematological cancer research. The characteris-
proliferation of DND1, a PTEN+/+ cell line with mutated NOTCH1, tics of the bone marrow depend upon a complex network of cells of
was hampered by DBZ and phenotypically rescued by treatment with hematopoietic and mesenchymal lineages, cellular signaling through
either methyl pyruvate or dimethyl αKG, membrane permeable chemokine receptors and adhesion molecules, vasculature, and the
sources of TCA cycle carbons.111 Finally, a comparison of stable dense protein meshwork of the extracellular matrix (ECM) (see Tabe
isotope tracing using [13C6]‐glucose or [13C5]‐glutamine in NOTCH1‐ and Konopleva116 for a detailed review). This microenvironment pro-
induced primary ALL cells revealed that glutaminolysis is the major vides cues for cellular homing, quiescence, self‐renewal, differentia-
source of carbons for mitochondrial metabolism; thus, this pathway tion, and proliferation, all of which become dysregulated in LSCs and
is a promising target for metabolic manipulation in the treatment of leukemia cells. One aspect of the niche with substantial metabolic
Notch‐implicated T‐ALL cases.111,112 However, this reliance on gluta- implications is oxygen tension, as hypoxia is a critical regulator of
mine‐dependent anaplerosis has been observed to decrease in cells HIF‐1α activity and subsequent metabolic programs. Indeed, hypoxia
56
that have acquired drug resistance. These metabolic changes occur can contribute to chemoresistance in AML cells117,118 and potentially
concomitantly with increased glycolysis and altered FAO, further serve as a prognostic marker.117 In addition, lower oxygen tension can
evidencing the role of metabolism in responses to environmental influence interactions between transformed and stromal cells by
stimuli. Interestingly, CCRF‐CEM cells are able to acquire resistance upregulating the expression of important adhesion molecules119,120
to danorubicin in part due to increased expression of DNAJC15, which to attract cancer cells to hypoxic environments. As age is an important
encodes for the HSP40 family member methylation‐controlled J pro- risk factor for leukemic ongogenesis (seer.cancer.gov), it is important
tein (MCJ). This protein has been found to modulate mitochondrial to note the age‐associated increase in bone marrow adipocytes, which
respiration via the disruption of mitochondrial supercomplexes,113,114 can influence oncogenesis through chemokine signaling, as well pro-
thereby decreasing mitochondrial utilization and explaining a shift viding fatty acid substrates for FAO,121,122 a key metabolic adaptation
towards glycolysis in drug resistance. observed in some leukemic cells and discussed earlier in this review.
In another metabolic intervention approach to targeting ALL Additional niche metabolites can also contribute to HSC and cancer
cells, thiopurine compounds, such as 6‐mercaptopurine (also termed cell behavior, with studies looking at the levels of arginine123 and
purinethol) and 6‐thioguanine (or tioguanine), are utilized in the treat- asparagine124 on leukemic cell response. Valine has also been recently
ment of ALL for their ability to stall DNA replication and induce cell revealed as an important effector of the bone marrow microenviron-
death. Such thiopurines have sufficient structural similarities to hypo- ment,125 although more work will be required to elucidate implications
xanthine and guanine, respectively, to be converted into nucleotides for oncogenesis.
and incorporated into DNA and RNA; however, they impede protein As the microenvironment promotes oncogenesis, transformed
machinery involved in processes like repair, replication, and transla- cells also alter the surrounding microenvironment into a pro‐onco-
tion, ultimately causing cytotoxicity. A recent study investigated ALL genic niche and contribute to adaptive oncogenesis.126 The adapta-
resistance to thiopurines by clonal selection of ALL cells resistant to tions of LSCs enable these cells to outcompete HSCs and take
each of the two thiopurines described and found through exome control of the bone marrow niche. AML cells can transform the niche
sequencing that the insensitivity of such cells to the thioguanine into a proleukemic environment by promoting osteogenic differentia-
nucleotides occurs in the presence of mutated hypoxanthine‐guanine tion of mesenchymal stem cells127 or by secreting exosomes.128 Leu-
phosphoribosyltransferase (HGPRT), the enzyme responsible for kemic blasts can also reprogram surrounding adipocytes to
converting hypoxanthine to inosine monophosphate and guanine to upregulate lipase activity thereby providing substrates for FAO.55 Adi-
115
guanosine monophosphate. pocytes are also a source of proinflammatory cytokines,129 some of
In total, ALL tumor cells are characterized by a high metabolic rate which can alter the balance between normal and pathologic hemato-
that implies a reliance on amino acids (specifically asparagine) and a poietic cell behavior.130-132
robust supply and utilization of glucose through glycolysis and the These effectors may also influence the surrounding ECM, which
PPP. Recent efforts have uncovered the metabolic rewiring that can harbor chemosignaling and mechanosignaling cues, the latter of
underlies transformation in these cells along with features of ALL cells which are based upon ECM stiffness and architecture.133,134 Indeed,
that distinguish their biochemistry from their myeloid counterparts, three‐dimensional mechanosignaling can influence leukemic cell
providing new opportunities for treating this disease in a selective response to therapy.135 ECM components tenascin C136 and
and effective manner. A challenging aspect of ALL treatment, not laminins137 contribute to hematopoietic cycling and homing to the
unlike for other cancers, is the potential and likely presence of as‐ bone marrow. ECM remodeling through the activities of matrix
10 of 13 NEMKOV ET AL.

metalloproteinases has been shown to play a role in the pathogenesis 3. Patti GJ, Yanes O, Siuzdak G. Innovation: metabolomics: the apogee
of multiple myeloma. 138
The resulting architecture, as well as the indi- of the omics trilogy. Nat Rev Mol Cell Biol. 2012;13(4):263‐269.

vidual components present in the bone marrow niche, affects tissue 4. Takubo K, Goda N, Yamada W, et al. Regulation of the HIF‐1alpha
139 level is essential for hematopoietic stem cells. Cell Stem Cell.
stiffness and mechanosignaling through axes such as YAP/TAZ.
2010;7(3):391‐402.
This transduction pathway is also tied to nutrient signaling140 and
5. Takubo K, Nagamatsu G, Kobayashi CI, et al. Regulation of glycolysis
nucleotide metabolism.141 Interestingly, while YAP/TAZ is mediated by Pdk functions as a metabolic checkpoint for cell cycle quiescence
by mevalonate metabolism, the cholesterol‐lowering drug lovastatin in hematopoietic stem cells. Cell Stem Cell. 2013;12(1):49‐61.
can inhibit LSCs in coculture with MSCs,142,143 highlighting a possible 6. Ito K, Carracedo A, Weiss D, et al. A PML‐PPAR‐delta pathway for
fatty acid oxidation regulates hematopoietic stem cell maintenance.
connection between the ECM and LSC metabolism.
Nat Med. 2012;18(9):1350‐1358.
In summary, the investigations reviewed here aim not only to elu-
7. Wilkinson AC, Yamazaki S. The hematopoietic stem cell diet. Int J
cidate the fine tuning of leukemic cell metabolism particularly in con- Hematol. 2018.
trast to each type's healthy counterpart cells but also to expand on 8. Pietras EM, Reynaud D, Kang YA, et al. Functionally distinct subsets
the larger context of how the leukemia subtypes differ. Such a of lineage‐biased multipotent progenitors control blood production
detailed understanding will improve treatment approaches and pro- in normal and regenerative conditions. Cell Stem Cell.
2015;17(1):35‐46.
vide new technical approaches to investigate metabolism at the levels
9. Pietras EM. Inflammation: a key regulator of hematopoietic stem cell
of genes, proteins, and metabolites. Although the ECM in particular
fate in health and disease. Blood. 2017;130(15):1693‐1698.
has been challenging to study from a systems level due to inherent dif-
10. Pietras EM, Mirantes‐Barbeito C, Fong S, et al. Chronic interleukin‐1
ficulties in quantifying insoluble proteins by liquid chromatography exposure drives haematopoietic stem cells towards precocious mye-
and mass spectrometry, innovations in sample preparation and han- loid differentiation at the expense of self‐renewal. Nat Cell Biol.
dling144,145 will help to reveal unique holistic changes to the bone 2016;18(6):607‐618.

marrow microenvironment in the future. While current therapeutic 11. Karigane D, Takubo K. Metabolic regulation of hematopoietic and
leukemic stem/progenitor cells under homeostatic and stress condi-
development has centered upon direct leukemic cell targeting,
tions. Int J Hematol. 2017;106(1):18‐26.
expanding this focus to include ECM dynamics in combination with
12. Testa U, Labbaye C, Castelli G, Pelosi E. Oxidative stress and hypoxia
metabolic reprogramming during oncogenesis holds promise for the in normal and leukemic stem cells. Exp Hematol. 2016;44(7):540‐560.
development of new classes of leukemia therapies. 13. Yu VWC, Yusuf RZ, Oki T, et al. Epigenetic memory underlies cell‐
autonomous heterogeneous behavior of hematopoietic stem cells.
Cell. 2016;167(5):1310‐22.e17.
ACKNOWLEDGEMEN TS
14. Jordan CT. The leukemic stem cell. Best Pract Res Clin Haematol.
AD is a recipient of the Boettcher Webb‐Waring Biomedical Research 2007;20(1):13‐18.
Award. TN is a recipient of US National Institutes of Health grant NIH 15. Herault A, Binnewies M, Leong S, et al. Myeloid progenitor cluster
T32 HL007171. The authors are grateful to Dr. Courtney Jones formation drives emergency and leukaemic myelopoiesis. Nature.
(University of Colorado Denver—Department of Hematology) for 2017;544(7648):53‐58.

helpful discussions and feedback. 16. Herndon TM, Chen SS, Saba NS, et al. Direct in vivo evidence for
increased proliferation of CLL cells in lymph nodes compared to bone
marrow and peripheral blood. Leukemia. 2017;31(6):1340‐1347.
CONF LICT OF INT E RE ST
17. Vangapandu HV, Ayres ML, Bristow CA, et al. The stromal microenvi-
Although unrelated to the contents of the manuscript, the authors ronment modulates mitochondrial oxidative phosphorylation in
disclose that AD and TN are members of Omix Technologies, Inc. chronic lymphocytic leukemia cells. Neoplasia. 2017;19(10):762‐771.
18. Daniel C, Mato AR. BCL‐2 as a therapeutic target in chronic lympho-
cytic leukemia. Clin Adv Hematol Oncol. 2017;15(3):210‐218.
AUT HORS' CONT R IBUT ION
19. Mayer RL, Schwarzmeier JD, Gerner MC, et al. Proteomics and meta-
All authors had full access to the data in the study and take bolomics identify molecular mechanisms of aging potentially
responsibility for the integrity of the data and the accuracy of the data predisposing for chronic lymphocytic leukemia. Mol Cell Proteomics.
2018;17:290‐303.
analysis. Conceptualization, T.N. and J.A.R. F.M.L.; Writing ‐ Original
20. Koczula KM, Ludwig C, Hayden R, et al. Metabolic plasticity in CLL:
Draft, T.N. and J.A.R. F.M.L.; Writing ‐ Review & Editing, T.N., A.D.,
adaptation to the hypoxic niche. Leukemia. 2016;30(1):65‐73.
and J.A.R. F.M.L.; Visualization, T.N., A.D., and J.A.R. F.M.L.; Supervi-
21. Valsecchi R, Coltella N, Belloni D, et al. HIF‐1alpha regulates the
sion, J.A.R. F.M.L.; Funding Acquisition, T.N. and A.D. F.M.L. interaction of chronic lymphocytic leukemia cells with the tumor
microenvironment. Blood. 2016;127(16):1987‐1997.
ORCID 22. Kontos CK, Papageorgiou SG, Diamantopoulos MA, et al. mRNA
overexpression of the hypoxia inducible factor 1 alpha subunit gene
Julie A. Reisz http://orcid.org/0000-0002-7296-4963 (HIF1A): an independent predictor of poor overall survival in chronic
lymphocytic leukemia. Leuk Res. 2017;53:65‐73.
RE FE R ENC E S 23. Jitschin R, Braun M, Qorraj M, et al. Stromal cell‐mediated glycolytic
switch in CLL cells involves Notch‐c‐Myc signaling. Blood.
1. Fiehn O. Metabolomics—the link between genotypes and phenotypes.
2015;125(22):3432‐3436.
Plant Mol Biol. 2002;48(1–2):155‐171.
24. Zhou Y, Hileman EO, Plunkett W, Keating MJ, Huang P. Free
2. Johnson CH, Ivanisevic J, Siuzdak G. Metabolomics: beyond radical stress in chronic lymphocytic leukemia cells and its role in
biomarkers and towards mechanisms. Nat Rev Mol Cell Biol. cellular sensitivity to ROS‐generating anticancer agents. Blood.
2016;17(7):451‐459. 2003;101(10):4098‐4104.
NEMKOV ET AL. 11 of 13

25. Zhang W, Trachootham D, Liu J, et al. Stromal control of cystine 45. Kuntz EM, Baquero P, Michie AM, et al. Targeting mitochondrial
metabolism promotes cancer cell survival in chronic lymphocytic oxidative phosphorylation eradicates therapy‐resistant chronic
leukaemia. Nat Cell Biol. 2012;14(3):276‐286. myeloid leukemia stem cells. Nat Med. 2017;23(10):1234‐1240.
26. Cramer SL, Saha A, Liu J, et al. Systemic depletion of L‐cyst(e) ine with 46. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia.
cyst(e) inase increases reactive oxygen species and suppresses tumor New Eng J Med. 2015;373(12):1136‐1152.
growth. Nat Med. 2017;23(1):120‐127. 47. Dinner SN, Giles FJ, Altman JK. New strategies for relapsed acute
27. Cortez D, Reuther G, Pendergast A. The Bcr‐Abl tyrosine kinase myeloid leukemia: fertile ground for translational research. Curr Opin
activates mitogenic signaling pathways and stimulates G1‐to‐S phase Hematol. 2014;21(2):79‐86.
transition in hematopoietic cells. Oncogene. 1997;15:2333‐2342. 48. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World
28. Chai SK, Nichols GL, Rothman P. Constitutive activation of JAKs and Health Organization classification of myeloid neoplasms and acute
STATs in BCR‐Abl‐expressing cell lines and peripheral blood cells leukemia. Blood. 2016;127(20):2391‐2405.
derived from leukemic patients. J Immunol. 1997;159(10):4720‐4728. 49. Network TCGAR. Genomic and epigenomic landscapes of adult de
29. Pendergast AM, Quilliam LA, Cripe LD, et al. BCR‐ABL‐induced novo acute myeloid leukemia. New Eng J Med. 2013;368(22):
oncogenesis is mediated by direct interaction with the SH2 domain 2059‐2074.
of the GRB‐2 adaptor protein. Cell. 1993;75(1):175‐185. 50. Wang J‐H, Chen W‐L, Li J‐M, et al. Prognostic significance of
30. Skorski T, Bellacosa A, Nieborowska‐Skorska M, et al. Transformation 2‐hydroxyglutarate levels in acute myeloid leukemia in China. Proc
of hematopoietic cells by BCR/ABL requires activation of a PI‐3k/ Natl Acad Sci U S a. 2013;110(42):17017.
Akt‐dependent pathway. EMBO J. 1997;16(20):6151‐6161. 51. Musharraf SG, Siddiqui AJ, Shamsi T, Choudhary MI, Rahman AU.
31. Cilloni D, Saglio G. Molecular pathways: BCR‐ABL. Clin Cancer Res. Serum metabonomics of acute leukemia using nuclear magnetic
2012;18(4):930‐937. resonance spectroscopy. Sci Rep. 2016;6:30693.

32. Welner RS, Amabile G, Bararia D, et al. Treatment of chronic 52. Pabst T, Kortz L, Fiedler GM, Ceglarek U, Idle JR, Beyoglu D. The
myelogenous leukemia by blocking cytokine alterations found in plasma lipidome in acute myeloid leukemia at diagnosis in relation
normal stem and progenitor cells. Cancer Cell. 2015;27:671‐681. to clinical disease features. BBA Clin. 2017;7:105‐114.

33. Radich JP, Mauro MJ. Tyrosine kinase inhibitor treatment for newly 53. Perea G, Domingo A, Villamor N, et al. Adverse prognostic impact of
diagnosed chronic myeloid leukemia. Hematol Oncol Clin North Am. CD36 and CD2 expression in adult de novo acute myeloid leukemia
2017;31(4):577‐587. patients. Leuk Res. 2005;29(10):1109‐1116.

34. Breccia M, Abruzzese E, Castagnetti F, et al. Ponatinib as second‐line 54. Ye H, Adane B, Khan N, et al. Leukemic stem cells evade chemother-
treatment in chronic phase chronic myeloid leukemia patients in apy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell.
real‐life practice. Ann Hematol. 2018;97(9):1577‐1580. 2016;19:23‐37.
55. Shafat MS, Oellerich T, Mohr S, et al. Leukemic blasts program bone
35. Bentley J, Walker I, McIntosh E, Whetton AD, Owen‐Lynch PJ,
marrow adipocytes to generate a protumoral microenvironment.
Baldwin SA. Glucose transport regulation by p210 Bcr‐Abl in a
Blood. 2017;129(10):1320‐1332.
chronic myeloid leukaemia model. Br J Haematol.
2001;112(1):212‐215. 56. Staubert C, Bhuiyan H, Lindahl A, et al. Rewired metabolism in
drug‐resistant leukemia cells: a metabolic switch hallmarked by
36. Boren J, Cascante M, Marin S, et al. Gleevec (STI571) influences met-
reduced dependence on exogenous glutamine. J Biol Chem.
abolic enzyme activities and glucose carbon flow toward nucleic acid
2015;290(13):8348‐8359.
and fatty acid synthesis in myeloid tumor cells. J Biol Chem.
2001;276(41):37747‐37753. 57. Farge T, Saland E, de Toni F, et al. Chemotherapy‐resistant human
Acute myeloid leukemia cells are not enriched for leukemic stem cells
37. Gottschalk S, Anderson N, Hainz C, Eckhardt SG, Serkova NJ. Imatinib
but require oxidative metabolism. Cancer Discov. 2017;7(7):716‐735.
(STI571)‐mediated changes in glucose metabolism in human leukemia
BCR‐ABL‐positive cells. Clin Cancer Res. 2004;10(19):6661‐6668. 58. Skrtic M, Sriskanthadevan S, Jhas B, et al. Inhibition of mitochondrial
translation as a therapeutic strategy for human acute myeloid leuke-
38. Hirao T, Yamaguchi M, Kikuya M, Chibana H, Ito K, Aoki S. Altered
mia. Cancer Cell. 2011;20(5):674‐688.
intracellular signaling by imatinib increases the anti‐cancer effects of
tyrosine kinase inhibitors in chronic myelogenous leukemia cells. 59. Dang L, White DW, Gross S, et al. Cancer‐associated IDH1 mutations
Cancer Sci. 2018;109(1):121‐131. produce 2‐hydroxyglutarate. Nature. 2009;462:739.

39. Yang B, Wang C, Xie Y, Xu L, Wu X, Wu D. Monitoring tyrosine kinase 60. Ward PS, Patel J, Wise DR, et al. The common feature of leukemia‐
inhibitor therapeutic responses with a panel of metabolic biomarkers associated IDH1 and IDH2 mutations is a neomorphic enzyme activ-
in chronic myeloid leukemia patients. Cancer Sci. 2018;109:777‐784. ity aonverting alpha‐ketoglutarate to 2‐hydroxyglutarate. Cancer Cell.
2010;17(3):225‐234.
40. Karlikova R, Siroka J, Friedecky D, et al. Metabolite profiling of
the plasma and leukocytes of chronic myeloid leukemia patients. 61. Intlekofer AM, Dematteo RG, Venneti S, et al. Hypoxia induces pro-
J Proteome Res. 2016;15(9):3158‐3166. duction of L‐2‐hydroxyglutarate. Cell Metab. 2015;22(2):304‐311.

41. Wang K, Gao W, Dou Q, et al. Ivermectin induces PAK1‐mediated 62. Intlekofer AM, Wang B, Liu H, et al. L‐2‐Hydroxyglutarate production
cytostatic autophagy in breast cancer. Autophagy. 2016;12(12): arises from noncanonical enzyme function at acidic pH. Nat Chem
2498‐2499. Biol. 2017;13(5):494‐500.

42. Dou Q, Chen HN, Wang K, et al. Ivermectin induces cytostatic 63. Nadtochiy SM, Schafer X, Fu D, Nehrke K, Munger J, Brookes PS.
autophagy by blocking the PAK1/Akt Axis in breast cancer. Cancer Acidic pH is a metabolic switch for 2‐hydroxyglutarate generation
Res. 2016;76(15):4457‐4469. and signaling. J Biol Chem. 2016;291(38):20188‐20197.

43. Sharmeen S, Skrtic M, Sukhai MA, et al. The antiparasitic agent 64. Parker SJ, Metallo CM. Metabolic consequences of oncogenic IDH
ivermectin induces chloride‐dependent membrane hyperpolarization mutations. Pharmacol Ther. 2015;152:54‐62.
and cell death in leukemia cells. Blood. 2010;116(18):3593‐3603. 65. Sciacovelli M, Frezza C. Oncometabolites: unconventional triggers
of oncogenic signalling cascades. Free Radic Biol Med.
44. Wang J, Xu Y, Wan H, Hu J. Antibiotic ivermectin selectively induces
2016;100:175‐181.
apoptosis in chronic myeloid leukemia through inducing mitochon-
drial dysfunction and oxidative stress. Biochem Biophys Res Commun. 66. Figueroa ME, Abdel‐Wahab O, Lu C, et al. Leukemic IDH1 and IDH2
2018;497(1):241‐247. mutations result in a hypermethylation phenotype, disrupt TET2
12 of 13 NEMKOV ET AL.

function, and impair hematopoietic differentiation. Cancer Cell. all patients: final results of the international ALL trial (MRC UKALL
2010;18(6):553‐567. XII/ECOG E2993). Blood. 2008;111(4):1827‐1833.
67. Lu C, Ward PS, Kapoor GS, et al. IDH mutation impairs histone 87. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults
demethylation and results in a block to cell differentiation. Nature. after relapse of acute lymphoblastic leukemia (ALL); an MRC
2012;483:474. UKALL12/ECOG 2993 study. Blood. 2007;109(3):944‐950.
68. Losman JA, Looper RE, Koivunen P, et al. (R)‐2‐hydroxyglutarate is 88. Iacobucci I, Mullighan CG. Genetic basis of acute lymphoblastic leuke-
sufficient to promote leukemogenesis and its effects are reversible. mia. J Clin Oncol. 2017;35(9):975‐983.
Science. 2013;339(6127):1621‐1625. 89. O'Dwyer KM, Liesveld JL. Philadelphia chromosome negative B‐cell
69. Ragon BK, DiNardo CD. Targeting IDH1 and IDH2 mutations in acute acute lymphoblastic leukemia in older adults: current treatment and
myeloid leukemia. Curr Hematol Malig Rep. 2017;12(6):537‐546. novel therapies. Best Pract Res Clin Haematol. 2017;30(3):184‐192.
70. Chen WL, Wang JH, Zhao AH, et al. A distinct glucose metabolism 90. Valecha GK, Ibrahim U, Ghanem S, Asti D, Atallah JP, Terjanian T.
signature of acute myeloid leukemia with prognostic value. Blood. Emerging role of immunotherapy in precursor B‐cell acute lympho-
2014;124(10):1645‐1654. blastic leukemia. Expert Rev Hematol. 2017;10(9):783‐799.
71. Fuhrer T, Heer D, Begemann B, Zamboni N. High‐throughput, 91. Tan SH, Bertulfo FC, Sanda T. Leukemia‐initiating cells in T‐cell acute
accurate mass metabolome profiling of cellular extracts by flow lymphoblastic leukemia. Front Oncol. 2017;7:218.
injection‐time‐of‐flight mass spectrometry. Anal Chem. 2011;83(18): 92. Bongiovanni D, Saccomani V, Piovan E. Aberrant signaling pathways
7074‐7080. in T‐cell acute lymphoblastic leukemia. Int J Mol Sci. 2017;18(9).
72. Nemkov T, Hansen KC, D'Alessandro A. A three‐minute method for 93. Vadillo E, Dorantes‐Acosta E, Pelayo R, Schnoor M. T cell acute lym-
high‐throughput quantitative metabolomics and quantitative tracing phoblastic leukemia (T‐ALL): new insights into the cellular origins and
experiments of central carbon and nitrogen pathways. Rapid Commun infiltration mechanisms common and unique among hematologic
Mass Spectrom. 2017;31(8):663‐673. malignancies. Blood Rev. 2018;32(1):36‐51.
73. D'Alessandro A, Giardina B, Gevi F, Timperio AM, Zolla L. Clinical 94. Haskell CM, Canellos GP. L‐asparaginase resistance in human leuke-
metabolomics: the next stage of clinical biochemistry. Blood Transfus. mia—asparagine synthetase. Biochem Pharmacol. 1969;18(10):
2012;10(Suppl 2):s19‐s24. 2578‐2580.
74. Kiyoi H, Naoe T, Nakano Y, et al. Prognostic implication of FLT3 and 95. Marini BL, Perissinotti AJ, Bixby DL, Brown J, Burke PW. Catalyzing
N‐RAS gene mutations in acute myeloid leukemia. Blood. improvements in ALL therapy with asparaginase. Blood Rev.
1999;93(9):3074‐3080. 2017;31(5):328‐338.
75. Alvarez‐Calderon F, Gregory MA, Pham‐Danis C, et al. Tyrosine 96. Liang J, Shi P, Guo X, et al. A retrospective comparison of Escherichia
kinase inhibition in leukemia induces an altered metabolic state coli and polyethylene glycol‐conjugated asparaginase for the treat-
sensitive to mitochondrial perturbations. Clin Cancer Res. ment of adolescents and adults with newly diagnosed acute
2015;21(6):1360‐1372. lymphoblastic leukemia. Oncol Lett. 2018;15(1):75‐82.
76. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus 97. Cheng DH, Lu H, Liu TT, Zou XQ, Pang HM. Identification of risk
chemotherapy for acute myeloid leukemia with a FLT3 mutation. factors in high‐dose methotrexate‐induced acute kidney injury in
New Eng J Med. 2017;377(5):454‐464. childhood acute lymphoblastic leukemia. Chemotherapy. 2018;63(2):
77. Gregory MA, D'Alessandro A, Alvarez‐Calderon F, et al. ATM/G6PD‐ 101‐107.
driven redox metabolism promotes FLT3 inhibitor resistance in acute 98. Krull KR, Cheung YT, Liu W, et al. Chemotherapy pharmacodynamics
myeloid leukemia. Proc Natl Acad Sci U S a. 2016;113:E6669‐E6678. and neuroimaging and neurocognitive outcomes in long‐term survi-
78. Pei S, Minhajuddin M, Callahan KP, et al. Targeting aberrant glutathi- vors of childhood Acute lymphoblastic leukemia. J Clin Oncol.
one metabolism to eradicate human acute myelogenous leukemia 2016;34(22):2644‐2653.
cells. J Biol Chem. 2013;288:33542‐33558. 99. Cheung YT, Sabin ND, Reddick WE, et al. Leukoencephalopathy and
79. Pei S, Minhajuddin M, D'Alessandro A, et al. Rational design of a long‐term neurobehavioural, neurocognitive, and brain imaging out-
parthenolide‐based drug regimen that selectively eradicates acute comes in survivors of childhood acute lymphoblastic leukaemia
myelogenous leukemia stem cells. J Biol Chem. 2016;291: treated with chemotherapy: a longitudinal analysis. Lancet Haematol.
21984‐22000. 2016;3(10):e456‐e466.
80. Gallipoli P, Giotopoulos G, Tzelepis K, et al. Glutaminolysis is a meta- 100. Kanarek N, Keys HR, Cantor JR, et al. Histidine catabolism is a major
bolic dependency in FLT3 ITD acute myeloid leukemia unmasked by determinant of methotrexate sensitivity. Nature. 2018;559(7715):
FLT3 tyrosine kinase inhibition. Blood. 2018. blood‐2017‐12‐820035 632‐636.
81. Gregory MA, Nemkov T, Reisz JA, et al. Glutaminase inhibition 101. Vo TT, Lee JS, Nguyen D, et al. mTORC1 inhibition induces resistance
improves FLT3 inhibitor therapy for acute myeloid leukemia. Exp to methotrexate and 6‐Mercaptopurine in Ph(+) and Ph‐like B‐ALL.
Hematol. 2018;58:52‐58. Mol Cancer Ther. 2017;16(9):1942‐1953.
82. Sykes DB, Kfoury YS, Mercier FE, et al. Inhibition of dihydroorotate 102. Montecucco A, Zanetta F, Biamonti G. Molecular mechanisms of
dehydrogenase overcomes differentiation blockade in acute myeloid etoposide. EXCLI J. 2015;14:95‐108.
leukemia. Cell. 2016;167(1):171‐86.e15. 103. Yadav N, Kumar S, Marlowe T, et al. Oxidative phosphorylation‐
83. Pollyea DA, Jordan CT. Therapeutic targeting of acute myeloid leuke- dependent regulation of cancer cell apoptosis in response to antican-
mia stem cells. Blood. 2017;129(12):1627‐1635. cer agents. Cell Death Dis. 2015;6(11):e1969.
84. Pui C‐H, Relling MV, Downing JR. Acute lymphoblastic leukemia. New 104. Aoki S, Morita M, Hirao T, et al. Shift in energy metabolism caused by
Eng J Med. 2004;350(15):1535‐1548. glucocorticoids enhances the effect of cytotoxic anti‐cancer drugs
85. Pui CH, Pei D, Campana D, et al. A revised definition for cure of child- against acute lymphoblastic leukemia cells. Oncotarget. 2017;8(55):
hood acute lymphoblastic leukemia. Leukemia. 2014;28(12): 94271‐94285.
2336‐2343. 105. Fu X, Liu W, Huang Q, Wang Y, Li H, Xiong Y. Targeting mitochon-
86. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with stan- drial respiration selectively sensitizes pediatric acute lymphoblastic
dard‐risk acute lymphoblastic leukemia, the greatest benefit is leukemia cell lines and patient samples to standard chemotherapy.
achieved from a matched sibling allogeneic transplantation in first Am J Cancer Res. 2017;7(12):2395‐2405.
complete remission, and an autologous transplantation is less effec- 106. Chan LN, Chen Z, Braas D, et al. Metabolic gatekeeper function of
tive than conventional consolidation/maintenance chemotherapy in B‐lymphoid transcription factors. Nature. 2017;542(7642):479‐483.
NEMKOV ET AL. 13 of 13

107. Xiao G, Chan LN, Klemm L, et al. B‐cell‐specific diversion of glucose 128. Kumar B, Garcia M, Weng L, et al. Acute myeloid leukemia transforms
carbon utilization reveals a unique vulnerability in B cell malignancies. the bone marrow niche into a leukemia‐permissive microenvironment
Cell. 2018;173(2):470‐84.e18. through exosome secretion. Leukemia. 2017;32:575.
108. Hsieh AL, Walton ZE, Altman BJ, Stine ZE, Dang CV. MYC and 129. Hardouin P, Rharass T, Lucas S. Bone marrow adipose tissue: to be or
metabolism on the path to cancer. Semin Cell Dev Biol. not to be a typical adipose tissue? Front Endocrinol (Lausanne).
2015;43:11‐21. 2016;7(85). https://doi.org/10.3389/fendo.2016.00085
109. Palomero T, Ferrando A. Oncogenic NOTCH1 control of MYC and 130. Medyouf H, Mossner M, Jann JC, et al. Myelodysplastic cells in
PI3K: challenges and opportunities for anti‐NOTCH1 therapy in patients reprogram mesenchymal stromal cells to establish a trans-
T‐ALL. Clin Cancer Res. 2008;14(17):5314‐5317. plantable stem cell niche disease unit. Cell Stem Cell. 2014;14(6):
110. Weng AP, Ferrando AA, Lee W, et al. Activating mutations of 824‐837.
NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 131. Schepers K, Pietras EM, Reynaud D, et al. Myeloproliferative neopla-
2004;306(5694):269‐271. sia remodels the endosteal bone marrow niche into a self‐reinforcing
111. Herranz D, Ambesi‐Impiombato A, Sudderth J, et al. Metabolic leukemic niche. Cell Stem Cell. 2013;13(3):285‐299.
reprogramming induces resistance to anti‐NOTCH1 therapies in T cell 132. Camacho V, McClearn V, Patel S, Welner RS. Regulation of normal
acute lymphoblastic leukemia. Nat Med. 2015;21(10):1182‐1189. and leukemic stem cells through cytokine signaling and the microen-
112. Tzoneva G, Ferrando AA. Recent advances on NOTCH signaling in T‐ vironment. Int J Hematol. 2017;105(5):566‐577.
ALL. Curr Top Microbiol Immunol. 2012;360:163‐182. 133. Gattazzo F, Urciuolo A, Bonaldo P. Extracellular matrix: a dynamic
113. Hatle KM, Gummadidala P, Navasa N, et al. MCJ/DnaJC15, an microenvironment for stem cell niche. Biochim Biophys Acta.
endogenous mitochondrial repressor of the respiratory chain that 2014;1840(8):2506‐2519.
controls metabolic alterations. Mol Cell Biol. 2013;33(11):2302‐2314. 134. Knapik DM, Perera P, Nam J, et al. Mechanosignaling in bone health,
114. Champagne DP, Hatle KM, Fortner KA, et al. Fine‐tuning of CD8(+) T trauma and inflammation. Antioxid Redox Signal. 2014;20(6):970‐985.
cell mitochondrial metabolism by the respiratory chain repressor MCJ 135. Shin J‐W, Mooney DJ. Extracellular matrix stiffness causes systematic
dictates protection to influenza virus. Immunity. 2016;44(6): variations in proliferation and chemosensitivity in myeloid leukemias.
1299‐1311. Proc Natl Acad Sci U S a. 2016;113(43):12126‐12131.
115. Yang F, Fang H, Wang D, et al. HPRT1 activity loss is associated with 136. Nakamura‐Ishizu A, Okuno Y, Omatsu Y, et al. Extracellular matrix
resistance to thiopurine in ALL. Oncotarget. 2018;9(2):2268‐2278. protein tenascin‐C is required in the bone marrow microenvironment
116. Tabe Y, Konopleva M. Leukemia stem cells microenvironment. Adv primed for hematopoietic regeneration. Blood. 2012;119(23):
Exp Med Biol. 2017;1041:19‐32. 5429‐5437.

117. Griessinger E, Anjos‐Afonso F, Pizzitola I, et al. A niche‐like culture 137. Susek KH, Korpos E, Huppert J, et al. Bone marrow laminins influence
system allowing the maintenance of primary human acute myeloid hematopoietic stem and progenitor cell cycling and homing to the
leukemia‐initiating cells: a new tool to decipher their chemoresistance bone marrow. Matrix Biol. 2018;67:47‐62.
and self‐renewal mechanisms. Stem Cells Transl Med. 2014;3(4): 138. Panchabhai S, Kelemen K, Ahmann G, Sebastian S, Mantei J, Fonseca
520‐529. R. Tumor‐associated macrophages and extracellular matrix metallo-
118. Drolle H, Wagner M, Vasold J, et al. Hypoxia regulates proliferation of proteinase inducer in prognosis of multiple myeloma. Leukemia.
acute myeloid leukemia and sensitivity against chemotherapy. Leuk 2015;30:951.
Res. 2015;39(7):779‐785. 139. Dupont S, Morsut L, Aragona M, et al. Role of YAP/TAZ in
119. Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell traffick- mechanotransduction. Nature. 2011;474(7350):179‐183.
ing is regulated by hypoxic gradients through HIF‐1 induction of SDF‐ 140. Santinon G, Pocaterra A, Dupont S. Control of YAP/TAZ activity by
1. Nat Med. 2004;10(8):858‐864. metabolic and nutrient‐sensing pathways. Trends Cell Biol.
120. Fiegl M, Samudio I, Clise‐Dwyer K, Burks JK, Mnjoyan Z, Andreeff M. 2016;26(4):289‐299.
CXCR4 expression and biologic activity in acute myeloid leukemia are 141. Santinon G, Brian I, Pocaterra A, et al. dNTP metabolism links
dependent on oxygen partial pressure. Blood. 2009;113(7): mechanical cues and YAP/TAZ to cell growth and oncogene‐induced
1504‐1512. senescence. EMBO J. 2018.
121. Behan JW, Yun JP, Proektor MP, et al. Adipocytes impair leukemia 142. Hartwell KA, Miller PG, Mukherjee S, et al. Niche‐based screening
treatment in mice. Cancer Res. 2009;69(19):7867‐7874. identifies small‐molecule inhibitors of leukemia stem cells. Nat Chem
122. Carracedo A, Cantley LC, Pandolfi PP. Cancer metabolism: fatty acid Biol. 2013;9(12):840‐848.
oxidation in the limelight. Nat Rev Cancer. 2013;13(4):227‐232. 143. Seton‐Rogers S. Destroying leukaemia stem cell habitats. Nat Rev
123. De Santo C, Booth S, Vardon A, et al. The arginine metabolome in Cancer. 2013;13:821.
acute lymphoblastic leukemia can be targeted by the pegylated‐ 144. Hill RC, Calle EA, Dzieciatkowska M, Niklason LE, Hansen KC.
recombinant arginase I BCT‐100: targeting arginine metabolism in Quantification of extracellular matrix proteins from a rat lung scaffold
ALL. Int J Cancer. 2018;142:1490‐1502. to provide a molecular readout for tissue engineering. Mol Cell
124. Tiziani S, Kang Y, Harjanto R, et al. Metabolomics of the tumor micro- Proteomics. 2015;14(4):961‐973.
environment in pediatric acute lymphoblastic leukemia. PLoS One. 145. Barrett AS, Wither MJ, Hill RC, et al. Hydroxylamine chemical diges-
2013;8(12):e82859. tion for insoluble extracellular matrix characterization. J Proteome
125. Taya Y, Ota Y, Wilkinson AC, et al. Depleting dietary valine permits Res. 2017;16(11):4177‐4184.
nonmyeloablative mouse hematopoietic stem cell transplantation.
Science. 2016;354(6316):1152‐1155.
How to cite this article: Nemkov T, D'Alessandro A, Reisz JA.
126. Henry CJ, Marusyk A, DeGregori J. Aging‐associated changes in
hematopoiesis and leukemogenesis: what's the connection? Aging Metabolic underpinnings of leukemia pathology and treatment.
(Albany NY). 2011;3(6):643‐656. Cancer Reports. 2018;e1139. https://doi.org/10.1002/
127. Battula VL, Le PM, Sun JC, et al. AML‐induced osteogenic differenti- cnr2.1139
ation in mesenchymal stromal cells supports leukemia growth. JCI
Insight. 2017;2(13).