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Pharmacogenomics 353
https://t.me/med1917
Variants in PRPS1
Functionally relevant gain- of- function mutations in
another mediator of purine metabolism, PRPS1, were
recently identified in almost 7% of relapsed BCP- ALL
samples. PRPS1 encodes phosphoribosyl pyrophosphate
synthetase 1, which is a key enzyme in the de novo purine
synthesis (DNPS) pathway. In contrast to NT5C2 mutations, ultra- deep sequencing of serial bone marrow samples revealed that PRPS1 mutations were not detectable at
ALL diagnosis, but increased exponentially before clinical
relapse, which occurred early on- treatment. Expression of
gain- of- function variants in PRPS1 resulted in resistance
to thiopurine induced apoptosis. Functional investigations revealed, that the drug resistance PRPS1 variants
showed defective feed- back inhibition to adenosine- and
guanosine- diphosphates, which allowed for continuous
activation of DNPS, which in turn results in an increase of
intracellular hypoxanthine levels, that inhibit the activation of the thiopurine prodrugs (MP and TG) into their
active metabolites. These findings demonstrate that the
rare acquired somatic PRPS1 variants in ALL relapse
clones can drive thiopurine resistance via altering the
feedback inhibition of nucleotide synthesis and competitive inhibition of bioactivation of the prodrugs MP and
TG. One logical strategy to overcome this drug resistance
mechanism would be the inhibition of the continuously
activated DNPS pathway. Indeed, inhibition of GART
(phosphoribosylglycinamide formyltransferase), another
important enzyme of DNPS, via the small- molecule inhibitor lometrexol, reversed thiopurine drug resistance in
PRPS1- mutant cells invitro.
Clearly, much work is needed to further elucidate the
genomic drivers for treatment failure in ALL. The examples
of NT5C2, PRPS1, and TP53 R248Q however, provide evi-
dence that in the near future the routine use of genomic
interrogation techniques could help to early identify patients
with emergent relapse. This knowledge may allow tailoring
therapy accordingly, e.g. by drugging DNPS in clones that
develop resistance to thiopurines via PRPS1mediated DNPS
activation or by drugging highly active NT5C2 via the smallmolecule inhibitor CRCD2.
ALL- initiating abnormalities, which comprise the leukemic
clone and define subtype biology. These initiating lesions
typically cooperate with somatic secondary abnormalities,
which often involve B- cell development genes like IKAROS
zinc finger 1 (IKZF1) or paired box 5 (PAX5 ), which are present only in ALL subclones.
Two ALL subtypes have chimeric fusion genes that
involve transcription factor 3 (TCF3); namely, ALL with
t(1;19)/TCF3- PBX1 (~5% of ALL patients) and ALL with
t(17;19)/TCF3- HLF (~1% of ALL patients). Whereas children with TCF3- PBX1 ALLs have intermediate outcomes
with contemporary major leukemia study groups therapies,
almost all children with TCF3- HLF positive ALL have experienced early disease relapse and died, and affected patients
are considered eligible for addition of experimental therapies in first- line therapy. In an attempt to identify curative
treatment options for children with TCF3- HLF ALL, an
international collaborative study group set up a series of
genomic and functional studies, including an integrated
drug–response profiling approach. They first identified that
the chimeric fusion protein TCF3- HLF promotes cellular
transcriptional reprogramming toward a drug- resistant
immature state. Subsequently, they found that TCF3- HLF
xenografts are highly sensitive to the BCL2 (B- cell CLL/
lymphoma 2)- targeting drug venetoclax. Combination of
venetoclax with conventional chemotherapy induced durable remissions in patient- derived xenografts; and subsequently a stratum allowing for combination of venetoclax
with standard ALL therapy in the setting of a pediatric phase
I/II study (NCT03236857) was implemented, and the results
are pending.
Moreover, TCF3- HLF ALL has a strong homogeneous
expression of CD19, and therefore these patients may benefit
from CD19- directed therapies. Indeed, durable molecular
remissions lasting 1317, 1292, 1245, and 342 days, have been
reported in a small series of patients with TCF3- HLF after
treatment that included the bispecific T- cell engager molecule blinatumomab and stem cell transplantation; and the
value of CDthis highest risk patient sub- cohort.
19 directed therapies is currently evaluated in
Optimization of therapy in children with
TCF3-
HLF ALL
One typical feature of childhood ALL is the subtype- defining
presence of chromosomal aberrations like translocations and
gross aneuploidies. Translocations, such as t(12;21), t(9;22),
t(1;19), or t(17;19) and the corresponding gene fusions
ETV6- RUNX1, BCR- ABL1, TCF3- PBX1, or TCF3- HLF,
which mainly involve genes that play an important role in
hematopoietic development, are considered to be primary
本书版权归John Wiley & Sons Inc.所有
Pharmacogenomics tooptimize oral
antithrombotic therapy
Cardiovascular diseases (CVDs) are the most common cause
of death, accounting for ~17.9 million deaths in 2019 (of
these deaths, 85% were due to heart attack and stroke; https://
www.who.int/news- room/fact- sheets/detail/cardiovasculardiseases- (cvds)). Arterial or venous thrombotic events are
major fatal complications of CVDs, and can be prevented via
antithrombotic medications, like oral anticoagulants and
antiplatelet therapies.
354 Molecular Hematology
Reduced vitamin
Active blood clotting proteins
Target Metabolism
https://t.me/med1917
Coumarins and variants in CYP2C9 and VKORC1
Although treatment trials demonstrated a favorable efficacy
and safety profile of direct (non- vitamin K antagonist) oral
anticoagulants (DOACs), which either directly inhibit
thrombin (e.g. dabigatran) or factor Xa (e.g. rivaroxaban,
apixaban, and edoxaban), millions of patients still take
coumarins to prevent thromboembolic events in chronic
conditions such as atrial fibrillation, deep venous thrombosis,
pulmonary emboli, acute myocardial infarction, stroke, and
disease and/or replacement of heart valves. The oral anticoagulants of the coumarin type, warfarin (used in the UK and the
USA), acenocoumarol, and phenprocoumon (preferentially
used in continental Europe), have similar pharmacodynamic
properties but differences in half- life, and act by inhibiting
the activation of vitamin K–associated clotting factors. A very
narrow therapeutic index, with risk of serious hemorrhage
if overcoagulated and thrombosis if undercoagulated and
interindividual variability in response to coumarins, necessitates individualization of treatment, which is based primarily on monitoring prothrombin time and calculation of the
International Normalized Ratio (INR). Whereas INR is
helpful in tailoring coumarin maintenance therapy, prospective studies have identified coumarin induction therapy as
the period when the INR is most likely to be out of range and
when the rate of iatrogenic ADRs is greatest.
Many factors have been identified as affecting the degree
of anticoagulation achieved by coumarins, including patient
age (lower dose requirement in the elderly), gender, body
size, ethnicity, diet (particularly vitamin K intake), cigarette
smoking, disease (e.g. liver diseases), and coadministration
of other drugs (particularly those which inhibit the activity
of CYP2C9). Polymorphisms in genes that affect the pharmacokinetics (CYP2C9, and to a lesser extent other CYP
enzymes) and pharmacodynamics (VKORC1) of coumarins,
however, have been shown to act as major determinants of
coumarin dosage requirements.
Coumarins are a racemic mixture of R-
and S- enantiomers
that differ in their patterns of metabolism and in their
potency of pharmacodynamic effect. For example, it has
been suggested that S- warfarin accounts for up to 70% of the
overall anticoagulation response of warfarin. After oral
administration, warfarin is completely absorbed and bound
to albumin (99%) in plasma. Free warfarin is taken up into
liver cells, where it is biologically active and either inhibits
VKORC1 or is catabolized by cytochrome P450 isoenzymes
(Figure23.4).
Variants in CYP2C9
A number of CYP isoforms contribute to warfarin metabolism;
however, hydroxylation by CYP2C9 is the most important
inactivation pathway of the pharmacologically more relevant
S- warfarin. CYP2C9 is the principal CYP2C isoenzyme in
the human liver, and it is involved in the oxidative metabolism of several clinically important medications, including
oral anticoagulants, phenytoin, and various non- steroidal
anti- inflammatory drugs. Numerous polymorphic alleles
(CYP2C9*1 to CYP2C9*71) have been identified for the
known CYP2C9 gene, according to the Pharmacogene
Variation Consortium (PharmVar) database (https://www.
pharmvar.org/gene/CYP2C9), at least half of which are associated with diminished enzyme activity. The two most common
CYP2C9 variants are CYP2C9*2 and CYP2C9*3. As with most
polymorphisms, there are differences in the frequency of polymorphic CYP2C9 alleles among different ethnic groups. In
Europeans, the overall allelic frequency of CYP2C9*2 is about
10–20%, and that of CYP2C9*3 is about 5–10%. The *2 and *3
variants are very rare in African Americans and Asians; 95% of
these persons express the wild- type genotype *1/*1 (i.e. extensive metabolizers). Compared with the wild- type enzyme
activity of CYP2C9*1, the enzyme activity of the CYP2C9*2
variant is reduced by about 30–50%, and the CYP2C9*3 variant activity is reduced by 90% invitro.
Epoxide
reductase
VKORC1
本书版权归John Wiley & Sons Inc.所有
Glutamic acid
K
Carboxylase
Vitamin K epoxide
Gamma-Carboxyglutamic acid
S-warfarin
CYP2C9
S-OH-warfarin
Warfarin
Cytochrome
P450
R-warfarin
CYP1A2
CYP3A4
R-OH-warfarin
Figure23.4 Mechanism of action of warfarin.
Theracemic mixture of r- and the more potent
s- warfarin inhibits the reductase in the vitamin K
cycle, impairing the synthesis of active vitamin
K- dependent clotting factors in liver cells and
causing bleeding. The cytochrome P450 isoenzyme
CYP2C9 (and to a lesser extent CYP3A4 and
CYP1A2) and vitamin K epoxide reductase complex
1 (VKORC1) genotypes influence warfarin dose
requirement.
Pharmacogenomics 355
https://t.me/med1917
Variants in VKORC1
VKORC1 regenerates reduced vitamin K for another cycle of
catalysis, essential for the γ- carboxylation of the vitamin K–
dependent clotting factors II, VII, IX, and X (Figure23.4).
The identification of common variants in VKORC1 has
emerged as one of the most important genetic factors determining coumarin dose requirements. Main VKORC1 haplo-
types include the reference haplotype (wild- type) VKORC1*1,
the low- dose coumarin haplotype VKORC1*2, and the high-
dose coumarin haplotypes VKORC1*3 and VKORC1*4. The
significantly higher average warfarin requirement in Africans
is in line with the significantly lower occurrence of the
low- dose coumarin VKORC1*2 haplotype in Africans. Overall,
the hereditary pharmacodynamics factor VKORC1 may
explain about 25% of the variance in coumarin dose requirement, compared with 5–10% for the hereditary pharmacokinetic factor CYP2C9 alone. CYP2C9 and VKORC1 genotypes
have been incorporated into dosing algorithms in order to
estimate the appropriate coumarin starting dose, and in 2010
the FDA updated the warfarin drug label and suggested that
VKORC1 and CYP2C9 genotypes should be taken into consideration when the drug is prescribed. Dosing algorithms
and more details are available at https://www.pharmgkb.org/
gene/PA133787052/prescribingInfo and www.warfarindosing.org. Randomized controlled clinical trials, such as the
European Pharmacogenetics of Anticoagulant Therapy (EUPACT) and the US Clarification of Optimal Anticoagulation
through Genetics (COAG) trials, have investigated the
potential benefit of genotype- based strategies for initiating
coumarin therapy. Although the use of genotype- based algorithms has resulted in a greater percentage of time in therapeutic range than standard- fixed dosing in the EU- PACT
trial, no reductions of severe ADRs like stroke or bleeding
were reported with the pharmacogenomic dosing. These trials, however, were not powered for the pharmacodynamics
endpoints bleeding or thromboembolic events, and the
Genetics Informatics Trial (GIFT) of Warfarin to Prevent
Deep Venous Thrombosis investigated this topic. Patients
undergoing elective hip or knee arthroplasty were treated
with perioperative warfarin, and genotype-
guided warfarin
dosing, compared with clinically guided dosing, reduced the
combined risk of major bleeding, INR of 4 or greater, venous
thromboembolism, or death. Of note is that results from the
Effective Anticoagulation with Factor Xa Next Generation in
Atrial Fibrillation–Thrombolysis in Myocardial Infarction
48 (ENGAGE AF- TIMI 48) trial (which enrolled more than
14 000 patients with atrial fibrillation) provided evidence
that testing for VKORC1 and CYP2C9was able to identify
patients who are more likely to bleed with warfarin therapy.
This information could be used to optimize choice of oral
anticoagulant therapy; that is, to use edoxaban in patients
who are sensitive (typically 1–2 variant alleles) or highly
sensitive (typically 3–4 variant alleles) to warfarin. The feasibility of implementing genotype-
guided dosing was recently
demonstrated in three- anticoagulation clinics in northern
England. Using the EU- PACT trial algorithm, genotypeguided dosing resulted in greater time in the therapeutic
range in the first 3 months of therapy than standard dosing.
Clopidogrel and variants in CYP2C19
Platelets play a crucial role in thrombosis and the development of acute coronary syndromes (ACS) because a plateletrich thrombus forms at the site of the ruptured atherosclerotic
plaque. Thus, inhibition of platelet function is an effective
strategy in the treatment and prevention of thrombosis,
especially after percutaneous coronary interventions (PCIs).
The main classes of antiplatelet agents include aspirin, the
thienopyridines (clopidogrel and prasugrel), the nonthienopyridine P2Y purinergic receptor 12 (P2Y12) antagonists
(ticagrelor), and intravenous GPIIb/IIIa antagonists. Dual
platelet inhibition via aspirin and P2Y12 receptor antagonists is the guideline- approved standard of care in patients
with ACS and PCI with stenting. The newer P2Y12 receptor
antagonists prasugrel and ticagrelor have superior efficacy
compared with clopidogrel, but have a higher risk for bleeding and are more expensive.
Clopidogrel is an orally administered prodrug and the
response to it is heterogeneous (up to 20% of treated patients
do not respond to clopidogrel and are at risk for stent thrombosis, which usually results in sudden death or heart attack,
and a few patients have strong responses with bleeding).
Once absorbed, 85% of clopidogrel is inactivated via esterases, and only about 15% of the prodrug remains available
for a multistep activation via hepatic CYP enzymes. The
active drug selectively and irreversibly binds to the ADP
dependent P2Y12 receptor on thrombocytes and thereby
inhibits platelet activation and aggregation for the platelets’
lifespan, which is about 10 days. Candidate gene investigations identified loss-
of- function variants in the activating
enzyme CYP2C19 to significantly affect drug response. As
of June 2023, 39 variant CYP2C19 alleles (https://www.
pharmvar.org/gene/CYP2C19) have been identified; the
most important poor metabolizer (PM) alleles are *2 (~15%
in Europeans and Africans, ~30% in Asians) and the less frequent *3 (2–9% in Asians, less than 1% in Europeans and
Africans). The *17 gain- of- function allele results in enhanced
CYP2C19 enzyme activity, and can place these ultrametabolizing individuals at a higher risk for bleeding because
of increased drug activation.
Based on the results of clinical investigations, the FDA has
issued a “black box” warning for clopidogrel in regard to
reduced effectiveness in PM individuals (i.e. two loss- offunction CYP2C19 alleles), and genotyping for the important variants is widely available. The CPIC Dosing Guideline
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356 Molecular Hematology
https://t.me/med1917
for clopidogrel recommends an alternative antiplatelet therapy
(e.g. ticagrelor) for CYP2C19 poor (two loss- of- function
alleles) or intermediate (one loss- of- function allele) metabolizers if there is no contraindication (https://cpicpgx.org/
guidelines/guideline- for- clopidogrel- and- cyp2c19/). In a
draft guidance of May 2023, the UK National Institute for
Health and Care Excellence (NICE) stated, that “patients
who have had an ischemic stroke or transient ischemic attack
should take a genetic test to see whether they can be treated
with clopidogrel to reduce their risk of recurrence” (https://
www.nice.org.uk/guidance/indevelopment/gid- dg10054).
Genotyping for pathogenic CYP2C19 variant testing was
estimated to be around £139 a test; and if not available,
Genomadix Cube point- of- care test, which costs about £197
per test, was recommended.
Summary andchallenges forthe
future
As there are numerous non- genetic factors that influence
drug effects (e.g. compliance, nutritional factors, concurrent
medications), it is clear that pharmacogenomics will never
explain all interindividual variability in drug effects.
However, it was reported that over one year, ~58% of patients
in the UK received at least one drug, which is affected by
actionable variants in pharmacogenes, and the proportion of
people who carry at least one actionable pharmacogenomic
variant ranged from 91.4% (6 genes evaluated, USA) to
99.8% (11 genes evaluated, Estonia). There is also clear
evidence that pharmacogenomic models can help to improve
drug treatment in hematology by facilitating appropriate
dose individualization and optimal treatment selection. For
example, clinically actionable variants have been identified
in the TPMT, NUDT15, CYP2C9, CYP2C19 and VCORC1
genes, and the TPMT/NUDT15 and CYP2C9/VCORC1 as
well as the CYP2C19 models can be used to individualize
thiopurine and antithrombotic therapy a priori, thereby
reducing the risk of severe ADRs.
As of June 2023, the FDA lists >120 pharmacogenomic
associations (genemedical- devices/precision- medicine/table- pharmacogeneticassociations); and the table of pharmacogenomic biomarkers
in drug labeling contains >540 entries (https://www.fda.gov/
drugs/science- and- research- drugs/table- pharmacogenomicbiomarkers- drug- labeling). However, some barriers (e.g.
lack of studies that prove the cost benefit, lack of financial
reimbursement, etc.) still prevent the widespread use of
pre- emptive genetic testing (ideally by the use of multigene
panels) to guide drug therapy. Initiatives like the European
Pharmacogenetics Implementation Consortium (EU- PIC;
https://eu- pic.net/) and the Implementing Genomics in
Practice (IGNITE; https://gmkb.org/ignite-gdp/) networks
drug interactions, https://www.fda.gov/
are developing and testing pharmacogenomics implementation strategies. Moreover, the CPIC (https://cpicpgx.org/)
provides evidenceble guidelines that aim to support physicians to bring personalized medicine into clinical practice, by using an
individual’s genetic information to prescribe medications.
Electronic clinical decision support systems (CDSSs) can
make it feasible to utilize genetic information to prescribing
drugs; and CDSSs continuously improve and become more
widespread available.
One example for the successful implementation of a CDSS
evidence- based pharmacogenomics precision medicine
approach in routine clinical hematology was recently
reported from the SJCRH. Before the administration of
codeine, which is given to treat pain crisis in sickle cell disease (SCD), more than 600 patients with SCD were genotyped for CYP2D6 variants (CYP2D6 activates the prodrug
codeine to the active morphine). Interruptive alerts recommended against codeine for patients with high- risk CYP2D6
status (i.e. 7.1% ultra- rapid metabolizers who are at risk for
life- threatening ADRs; 1.4% poor metabolizers who are at
risk for insufficient pain control), and this example shows
how safety concerns can be reduced via preemptive
genotyping.
Moreover, the European Ubiquitous Pharmacogenomics
consortium has recently published the results of the prospective Preemptive Pharmacogenomic Testing for Preventing
Adverse Drug Reactions (PREPARE) study. In this study, the
effect of a genotype- guided drug prescribing strategy, using a
preemptive 12- pharmacogene panel (44 actionable variants)
approach in seven European centers with almost 7000 patients
randomly allocated to either standard care or genotypeguided care, was investigated. ADRs were significantly
reduced (30%) in the genotype- guided group, providing the
first randomized evidence of the utility of pharmacogenomic
panel- based testing.
Pharmacogenomics has evolved also as an important
component of precision medicine, especially in the context
of precision oncology. Besides the assessments of targetable
oncogenic drivers, growing interest has evolved in augmenting genomic testing with direct drug sensitivity testing
(pharmacotyping) in primary tumor samples. In the prospective Extended Analysis for Leukemia and Lymphoma
Treatment (EXALT) trial (NCT03096821) in Austria, an
image-
based single- cell functional precision medicine
(scFPM) approach was successfully used to guide therapy
choices for patients with aggressive hematologic cancers who
exceeded all standard therapy lines. High- content microscopy and automated image analysis was used to evaluate the
effects of 139 drugs on samples from heavily pretreated 143
patients with hematologic malignancies, without standardof- care options remaining. Pharmacotyping informed therapies were selected in a precision oncology panel and 54% of
based, peer- reviewed and publicly availa-
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Pharmacogenomics 357
https://t.me/med1917
such treated patients had at least 1.3 times longer progression free survival (PSF) than for previous therapies, and
21% had exceptional response, defined, as a PFS triple the
expected median response.
In a recent study from SJCRH, exvivo drug testing (18 drugs)
was performed in 805 children with newly diagnosed ALL,
and was integrated with invivo MRD load during therapy
and molecular subtype of blast cells. Six prognostic patients
clusters based on pharmacotypes including a subset of Tcell
ALL with poor prognosis were identified. The T cell subset
was sensitive to targeted therapies, highlighting opportunities
for further treatment individualization in childhood ALL.
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358 Molecular Hematology
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Chapter24
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Cancer stem cells
Sara Ali and Dominique Bonnet
Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, UK
The cancer stem cell concept, 359
The cell of origin, 360
Pre- leukemic stem cells, 360
The cancer stem cell concept
It was more than a century ago when the term stem cell
(Stammzelle) was coined by Haeckel to refer to the unicellular ancestor of multicellular organisms that stands at the bottom of a genealogical tree. Pappenheim later adopted the
term and applied it in its current meaning to describe the
precursor cell, which he postulated could give rise to all
blood cells. However, it was decades later that experimental
proof for the existence of hematopoietic stem cells (HSCs)
was provided. While studying the effects of radiation on
bone marrow function, Till and McCulloch made the seminal observation of hematopoietic colonies resembling nodules in the spleens of lethally irradiated mice that were
transplanted with limiting numbers of murine bone marrow
cells. Even more striking at the time was the observation that
upon retransplantation of these colonies into secondary
recipients, some were able to generate new multilineage colonies, indicating the ability of these cells to self- renew.
Akin to HSCs, the cancer stem cell (CSC) hypothesis posits that tumors assume a hierarchical organization in which a
subpopulation of cells with stem- like properties reside at the
apex, and have the capacity to self- renew and regenerate
tumors that recapitulate the parental tumor from which they
originate. The hierarchical model in cancer was first exemplified by the pioneering work of Professor J.E. Dick’s team,
which led to the identification of leukemic stem cells (LSCs)
in acute myeloid leukemia (AML). Leukemia- initiating cells
(LICs), functionally defined by their ability to repopulate
non- obese diabetic/severe combined immunodeficient
(NOD/SCID) mice, were found to represent only a small
proportion of leukemic cells (0.2–100/106 leukemic blasts)
and to reside in the same compartment as normal HSCs (lineage negative, CD34+CD38− subset), leading to the conclusion that AML likely arises from neoplastic transformation
occurring in primitive stem cells rather than their committed progeny. These findings sparked interest in exploring
CSC- targeted therapies, 361
Conclusion, 365
Further reading, 366
CSCs in various malignancies, and CSCs have since been
reported in solid tumors as well, providing further credence
to the CSC concept and extending its applicability beyond
hematological malignancies.
Although the CSC paradigm appears to hold true for different cancers, it certainly is not universal. One major caveat
that became apparent with the emergence of more permissive xenotransplantation models is the underestimated frequency of tumorstudies that employed mouse strains that still had significant
residual immune function. A typical example illustrating this
limitation is melanoma, which was thought, based on earlier
findings, to follow the CSC model. However, this was called
into question when it was subsequently reported that the frequency of cells with tumorigenic potential in melanoma
could be as high as 25%, arguing against there being a hierarchical organization. One possible explanation for this observation is provided by the stochastic model, which proposes
that all cells are biologically equivalent with equal clonogenic
potential to facilitate tumor initiation and growth, provided
they receive the appropriate cues, which may either be intrinsic or extrinsic. It must be noted, however, that the high frequency of TIC does not, in itself, indicate a stochastic pattern
of tumor development. What distinguishes the CSC paradigm from the stochastic model is that according to the former framework, only a unique subset of cells is endowed
with longon their intrinsic properties, be separated from non- TIC
cells. However, this is not possible in cancers that follow a
stochastic model, as all cells are equally permissive to transformation, and therefore TICs can be potentially found in
any cell fraction.
Nevertheless, the two models are by no means mutually
exclusive, and can operate simultaneously within a tumor.
Furthermore, several lines of evidence, based on findings in
normal and malignant tissues, point toward stemness being
a dynamic trait whereby cells can transition between a stem
term tumorigenic potential, and they can, based
initiating cells (TICs) reported in earlier
Molecular Hematology, Fifth Edition. Edited by Drew Provan and Hillard M. Lazarus.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
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359
360 Molecular Hematology
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cell and a differentiated cell state and vice versa. This notion,
known as bidirectional interconversion, provides an alternative explanation that can reconcile these two models.
The cell oforigin
Although often used interchangeably, the CSC is not necessarily the same as the cell of origin. The cell of origin refers to
the cell that sustains the first hit required for tumor initiation, but does not necessarily have stem cell properties to
allow it to sustain malignant growth. Equally important to
note is that CSCs need not be derived from their normal
stem cell counterparts, but are rather defined as cells with
stem cell properties and tumor- propagating capacity, regardless of whether they originated from a bona fide stem cell or
not. Indeed, there is significant evidence indicating that
CSCs can arise from downstream progenitor cells as they
undergo oncogenic transformation. In a study by Taussig
etal., sorted leukemic cells from patients with AML with the
progenitor phenotype CD34+CD38+ were able to induce leukemia in various immunodeficient mouse strains, indicating
that LSC activity is not restricted to the CD34+CD38− compartment as previously hypothesized. Furthermore, lentivirally transduced myeloid progenitors expressing the
mixed- lineage leukemia (MLL) fusion genes MLL- AF9 and
MLL- ENL have been shown to be able to initiate leukemia.
The results of global gene expression profiling of LSC populations in AML have also challenged the prevailing notion
that LSCs in AML largely arise from stem cells, and suggest
instead that LSCs in AML resemble lymphoid- myeloid
multipotent progenitors (LMPPs) and granulocytemacrophage progenitors (GMP) more closely than HSCs.
Although CSCs can originate from a differentiated progenitor, the cell of origin may still be a stem cell. For example, while
it is widely accepted that chronic myeloid leukemia (CML)
results from neoplastic transformation of an HSC by the BCRABL fusion gene, progression to blast crisis has been shown to
be driven by progenitor cells that have acquired stem- like
properties as a result of a catalog of events, including BCRABL amplification and B- catenin activation. Similarly, in AML
bearing the translocation t(8;21), resulting in the AML1/ETO
fusion gene, although the translocation is found in HSC, it is
not sufficient to induce leukemia, and the disease is instead
driven by cells with a progenitor phenotype.
Collectively, these data have led to a revised model that
unifies the CSC and stochastic models of tumor heterogeneity. According to this hypothesis, CSCs in the early stages
of tumor development are likely to follow the CSC model,
where CSCs account for a small proportion of the tumor
population, with the bulk comprising non- TIC. However,
as the disease progresses, these CSCs acquire advantageous
mutations which enhance their self- renewal ability, leading
to further expansion of the CSC pool, while impairing their
differentiation capacity. Consequently, as the disease
advances, the hierarchy becomes flatter and the tumor
becomes more homogenous, which would explain the high
frequency of CSCs reported in malignancies such as
melanoma.
Pre- leukemic stem cells
The earliest evidence supporting the concept of a preleukemic
state came from clonality studies utilizing X- chromosome
inactivation patterns in AML patients heterozygous for
glucose- 6- phosphate dehydrogenase (G6PD) deficiency. In
each of these patients, the leukemic blasts expressed the
same G6PD type, indicating that they arose from a single
cell, and in approximately 25% of the patients, the abnormal
clone at diagnosis persisted even after the attainment of complete morphological remission. Similar findings were
reported in AML patients harboring the translocation
t(8;21), who were found to have detectable levels of the
fusion transcript in peripheral blood, despite being in longterm remission. In recent years, corroborative evidence from
sequencing data has been provided by a number of groups.
Work from the Majeti lab demonstrated that in newly diagnosed patients with AML, mutations in epigenetic regulators
such as DNMT3a and ASXL1were frequently found in the
purified HSC population, whereas mutations in genes
involved in activated signaling and proliferation such as
FLT3 and KRAS/NRAS were not detectable, indicating that
the latter mutations were late events. Similarly, Shlush etal.
performed targeted sequencing of normal hematopoietic
stem, progenitor, and mature cell fractions in AML patients
at diagnosis, and found that, in contrast to genetic aberrations such as NPM1mutation, which was only detected in
the leukemic blasts, mutations in DNMT3a were found in
both the leukemic and non- leukemic compartments, indicating the presence of a predominant AML clone.
Indeed, genomic studies of large cohorts of individuals
with no history of hematological malignancy and normal
blood counts have revealed that somatically acquired mutations in hematopoietic cells are a frequent event in the aged
population, occurring in at least 10% of individuals above
the age of 70. Intriguingly, most of the mutations implicated
in this phenomenon, termed clonal hematopoiesis of indeterminate potential (CHIP), occur in epigenetic modifying
genes that are frequently mutated in myeloid malignancies
such as DNMT3a, TET2, and ASXL1. In addition to an
increased propensity for developing leukemia, individuals
with CHIP have an increased overall mortality.
As demonstrated in several studies, pre- leukemic clones
can evade chemotherapeutic interventions and persist or
leukemic clone ancestral to the
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Cancer stem cells 361
CHIP
LSC
Leukemia at diagnosis
(e.g. DNMT3a
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even expand in remission, and it has been shown that this is
more likely to occur among older patients, providing an
additional explanation for the poor outcome observed in this
group of patients. Additionally, persistence of pre- leukemic
mutations in remission in those who did not receive allogeneic transplant was found to be associated with an increased
risk for relapse. In a study by Ding and colleagues, wholegenome sequencing of paired samples from diagnosis and
relapse in patients with AML revealed two main patterns of
clonal evolution: in some patients, the relapse clone
descended from the dominant clone, which acquired additional mutations, whereas in others the dominant clone was
eradicated by treatment, but relapse arose from a subclone
that was present at diagnosis. Furthermore, in the study by
Shlush et al., analysis of early and late remission samples
from a patient who was still in remission at 3 years revealed
a progressive increase of DNMT3a allele frequency in most
of the progenitor and mature cells fractions over time. A
small proportion of the myeloid cells in the late remission
sample was also found to harbor both DNMT3a and
NPM1mutations, which could be explained by reexpansion
of the diagnostic clone or, alternatively, the NPM1mutation
could have been acquired independently within a preleukemic clone. Although there has so far been no solid
proof of relapse emerging from a pre- LSC, this route to
relapse remains plausible. From a clinical perspective, the
persistence of pre- LSCs in remission raises the question of
whether testing for minimal residual disease should include
monitoring for pre- leukemic mutations and not only the
“driver” mutations present in leukemic blasts and LSCs, and
whether progressive increase in pre- leukemic burden during
remission would warrant early treatment prior to the emergence of frank leukemia (see Figure24.1).
CSC- targeted therapies
Targeting cell surface antigens
Since HSCs and LSCs share the cell surface phenotype
CD34+/CD38−, several groups have attempted to identify
markers that can accurately distinguish LSCs from HSCs, in
order to enable preferential targeting of LSCs while sparing
normal HSCs. Among the earliest identified LSC antigenic
candidates is interleukin- 3 alpha receptor (CD123), which is
strongly expressed in CD34+38− cells of patients with AML,
but virtually absent in the normal HSC counterpart. The
LSC functional capacity of this population has been verified
invivo, where they were able to engraft and induce leukemia
in NOD/SCID mice. Other putative LSC markers include
CD33, CLL- 1, Tim- 3, and CD47, which are currently being
pursued in clinical trials.
Various therapeutic approaches aimed at targeting surface
markers on LSCs have been explored, and one strategy has
been the use of antibody- drug conjugates (ADCs), consisting of
a monoclonal antibody linked to a therapeutic moiety, which
allows selective delivery of cytotoxic drugs to neoplastic cells
Secondary
mutations
TET2, ASXLI)
Figure24.1
hematopoiesis of indeterminate potential; HSC, hematopoietic stem cells; LSC, leukemic stem cells.
Model of clonal evolution from clonal hematopoiesis to disease development, and the different patterns of relapse. CHIP, clonal
Leukemia at
diagnosis
Normal HSC
Pre-leukemic HSC
LSC
Dominant clone
Minor clone
Treatment
(e.g. FLT3-ITD,
NPMI)
Remission
Relapse
Clonal
expansion
Dominant clone
Minor clone
LSC
Preleukemic HSC
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bearing the targeted antigen, with minimal impact on normal
tissues. A promising example of this class of drugs and the first
ADC to gain approval for clinical use in cancer is Gemtuzumab
ozogamicin (GO), comprising a humanized anti- CD33 antibody conjugated to the antitumor antibiotic calicheamicin.
After being initially withdrawn due to lack of clinical benefit
and safety concerns, GO was reapproved by the US Food and
Drug Administration (FDA) when subsequent clinical trials
using a lower dosing schedule showed that the addition of GO
to standard chemotherapy for treatment of patients with newly
diagnosed AML resulted in improved outcomes in terms of an
event- free survival which was nearly twice as long (median
event- free survival: 17.3 months versus 9.5 months).
Improvement in obtaining complete remission was also
observed when used in the relapse setting as well as a small,
but significant, increase in overall survival when used as a single agent in older patients who are ineligible for intensive
chemotherapy. It should be noted, however, that CD33 is not
an exclusive marker of LSC, but is also expressed in leukemic
blasts and myeloid progenitors, and thus far, it has not been
shown whether the improved outcome observed with GO
relates specifically to its effect on the LSC compartment or
merely the disease bulk.
Other approaches employing the immunophenotypic
properties of LSCs include bispecific antibodies, which
link the target pathogenic cell to a cytotoxic effector cell,
such as a T cell or natural killer cell, by simultaneously
engaging a tumor- specific antigen and a receptor expressed
on the cyto- toxic effector cell, thereby inducing cell death.
Adoptive cell therapy using chimeric antigen receptor
(CAR)- engineered T cells has also been pursued as an
LSC- targeting avenue.
Albeit promising, targeting LSCs by utilizing their aberrant immunophenotype has potential limitations, which
may hinder its clinical utility. One major concern relates to
the specificity of LSC marker, as it is crucial that an antigen
used to identify LSC is not expressed on normal HSC in
order to minimize toxicity. For instance, while CD33has
been thought not to be expressed in normal HSC, Taussig
eta l. reported CD33 expression in normal Lin
−
CD34+CD38−
fractions isolated from cord blood and healthy adult bone
marrow, which were able to repopulate NOD/SCID mice
and had self- renewal ability, as determined in serial transplantation assays. Indeed, CD33has been recently reported
to identify a subset of cells with serial repopulating capacity
within the most primitive HSC fraction. Furthermore, it is
well recognized that LSCs can be phenotypically heterogeneous and therefore an LSC- targeted therapy aimed at a
single antigen is unlikely to be able to eliminate all LSC
clones. The fact that LSCs undergo clonal evolution as the
disease progresses, and in response to selective pressure
exerted by treatment, adds yet another layer of complexity
to the picture.
Targeting CSC self- renewal
Aberrant activation of the Hedgehog (Hh) signaling pathway
has been reported in CSCs of various cancers, including
hematological malignancies. In a mouse model of CML, constitutive activation of Smoothend, a key component of the
Hh pathway, resulted in an increase in CML LSC frequency
leading to disease acceleration, while inhibition of Hh signaling by cyclopamine caused reduction in CML stem cells,
and this effect was maintained even in imatinib- resistant
CML- LSC.
The Wnt pathway effector β- catenin has also been implicated in the regulation of LSC. In murine AML models
driven by MLL- ENL or co- expression of the oncogenes
HOXA9 and MEIS1, β- catenin was required for transformation to AML. Furthermore, functional dependence of LSC
on the canonical Wnt signaling has been demonstrated in
T- cell acute lymphoblastic leukemia (T- ALL). In B- ALL,
suppression of CBP/catenin using a small molecule inhibitor
abrogated self- renewal of pre- B ALL cells, and promoted
their differentiation, thereby sensitizing them to chemotherapy. Similarly, LSCs in MLL- driven AML that have acquired
resistance to GSK3inhibitors could be resensitized by inhibiting β- catenin. Of note is that both Hh and β- catenin appear
dispensable for adult HSC function, rendering them attractive candidates for selective inhibition of LSCs.
The canonical Notch signaling pathway is another pivotal
player in maintaining self- renewal of LSC. There has been a
particular interest in targeting Notch in T- ALL due to the
high prevalence of Notch1mutations, which are estimated to
occur in more than 50% of patients. Treatment with a gamma
secretase inhibitor, which blocks Notch, has been shown to
abolish the leukemic- initiating stem cell activity in T- ALL
in vivo, regardless of mutational status. Other strategies to
target Notch include the use of monoclonal antibodies and
stapled peptides.
Targeting CSC survival
One of the earliest pieces of evidence implicating the nuclear
factor- kB (NF- kB) in CSC came from AML, where NF- kB
was found to be constitutively activated in the CD34+ fraction of AML cells but not in normal CD34+ HSCs, indicating
that reliance on NF- kB is an exclusive feature of LSCs.
Activation of NF- kB can occur through multiple routes,
including chromosomal/molecular aberrations, cytokine
signaling, or increased proteasomal activity. Inhibition of
NF- kB by a proteasome inhibitor was shown to induce apoptosis in AML cells in both the bulk and CD34+ fraction.
Additionally, inhibitors against the PI3/AKT/mtor pathway have been employed in AML. Constitutive activation of
phosphoinositide 3- kinase (PI3K) is necessary for the survival of AML, and reduction in AML LSC has been reported
in murine models treated with PI3K inhibitors. Intriguingly,
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