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| MYELOPROLIFERATIVE NEOPLASMS: NEW INSIGHTS IN THE CURRENT TREATMENT PARADIGM |

Myeloproliferative neoplasms: from origins to outcomes


Jyoti Nangalia1 and Anthony R. Green2,3

1
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom; 2Department of
Haematology, Cambridge Institute for Medical Research and Wellcome Trust/MRC Stem Cell Institute,
University of Cambridge, United Kingdom; and 3Department of Haematology, Addenbrooke’s Hospital,
Cambridge, United Kingdom

Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms.
The discovery of mutations in JAK2 over a decade ago heralded a new age for patient care as a consequence of improved

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diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin
brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological
basis for their excessive myeloproliferation. We are also beginning to understand the processes that lead to acquisition
of somatic mutations and the factors that influence subsequent clonal expansion and emergence of disease. Extended
genomic profiling has established a multitude of additional acquired mutations, particularly prevalent in myelofibrosis,
where their presence carries prognostic implications. A major goal is to integrate genetic, clinical, and laboratory features
to identify patients who share disease biology and clinical outcome, such that therapies, both existing and novel, can be
better targeted.

about how clonal populations of MPN cells might initially emerge. We


Learning Objectives conclude by considering the potential implications for clinical practice.
• Understand the central role of aberrant JAK-STAT signaling
in driving the myeloproliferative phenotype Phenotypic driver mutations converge on
• Appreciate the factors that may influence the earliest stages of
JAK-STAT signaling
MPN emergence
The cardinal and mutually exclusive mutations in MPNs occur in
• Become familiar with the range of additional mutations in
JAK2, CALR, or MPL, referred to herein as the “phenotypic drivers”
MPN and their role in disease biology
because of their role in driving the myeloproliferative phenotype. In
2005, a single point mutation resulting in JAK2V617F was identified
in most patients with PV and half of those with ET or MF.2-5 JAK2 is
intimately associated with the cytoplasmic portions of receptors for
Introduction key hematopoietic cytokines, such as erythropoietin, thrombopoietin
The myeloproliferative neoplasms (MPNs) are clonal hematopoietic (TPO), and granulocyte colony-stimulating-factor. Normal JAK2
disorders characterized, in chronic phase, by an overproduction of dif- functions to activate intracellular signaling pathways following li-
ferentiated hematopoietic cells. The Philadelphia-negative MPNs include gand binding; however, JAK2V617F is rendered constitutively active.
3 main diseases: polycythemia vera (PV), essential thrombocythemia The mutation is understood to result in loss of the normal inhibitory
(ET), and myelofibrosis (MF).1 The last decade has witnessed dramatic function provided by the pseudokinase (JH2) domain upon the active
advances in our understanding of the molecular and cellular basis of (JH1) kinase domain—in this model, it is unclear whether the dis-
excessive myeloproliferation, and this has led to the development and rupted JH1/JH2 interface occurs within an individual JAK2 molecule
therapeutic use of novel targeted treatments, such as JAK inhibitors. More or between JAK2 dimers.6 The mutation may also result in direct
recently, we have begun to accumulate tantalizing insights into the origins activation of the JH1 domain via an SH2-JH2 linker.7 Subsequent
of these cancers, as well as the factors that drive later disease evolution. downstream activation of intracellular signaling occurs via signal
transducer and activator of transcription (STAT) protein signaling
Here, we review our current understanding of the evolution of MPNs, and, to a lesser extent, via mitogen-activated protein kinase and
from their origins to the emergence of disease and clinical progression. phosphoinositide 3-kinase signaling pathways, which together result
Our evolutionary narrative begins with a review of the molecular basis in excessive myeloid cell proliferation and differentiation.
of myeloproliferation in an established neoplastic clone. We then ad-
dress the factors that influence disease phenotypes in chronic phase and Additional genetic aberrations that perturb JAK-STAT signaling are
the basis for disease progression, after which we discuss what is known found in JAK2-unmutated MPNs. Mutations in the TPO receptor

This article was selected by the Blood and Hematology 2017 American Society of Hematology Education Program editors for concurrent submission to Blood and
Hematology 2017. It is reprinted with permission from Blood 2017, Volume 130.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Off-label drug use: None disclosed.

470 American Society of Hematology


c-MPL at W515, and less commonly at S505, are found in 5% to those induced by heterozygous mutations in MPL or JAK2. Such
8% of patients with ET and MF.8 These mutations are understood a hypothesis accords with the observation that patients with CALR-
to result in conformation changes to the receptor that mimic the mutated ET have an increased risk of myelofibrotic transformations,25
consequences of TPO binding, such that cytoplasmic JAK2 molecules particularly because excessive signaling via the MPL receptor is asso-
are brought into close proximity conducive for activation, trans- ciated with bone marrow fibrosis in transgenic mice26 and increased bone
phosphorylation, and ligand-independent intracellular signaling.9 As marrow reticulin is seen in patients with ET who have homozygous
might be expected from the normal function of MPL, these mutations MPL mutations.27 This would also be consistent with the observation
are associated with megakaryocyte proliferation, and disease pheno- that CALR mutations that result in a more extensive mutant C terminus,
types of ET and MF are recapitulated in murine models.8 for example, the type 1 52-bp deletion (L367fs*46) are more prevalent
among patients with MF10,11 and result in a more severe phenotype with
In 2013, mutations in calreticulin (CALR) were identified in most frequent MF transformation in a retroviral CALR-mutant mouse model.14
JAK2- or MPL-unmutated patients with ET or MF.10,11 CALR mu-
tations are insertions or deletions affecting the terminal exon of the In contrast to CALR or MPL, mutated JAK2 is pleiotropic and results
gene, which all result in a 11 base pair shift to the amino acid reading in numerous MPN phenotypes also recapitulated in JAK2V617F
frame of the DNA sequence, such that the mutant protein acquires mouse models.28 Many factors determine the phenotype that results

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a novel C terminus. The identification of such mutations was surprising after a JAK2 mutation. First, specific types of JAK2 mutation, for
because CALR was neither a cytokine receptor nor a known participant example, V617I, V617F, or mutations in exon 12, are associated with
in JAK-STAT signaling. CALR is best known for its housekeeping differing degrees of erythrocytosis vs thrombocytosis.18,29 Recent
function as a chaperone protein in the endoplasmic reticulum (ER), data demonstrate that this may be due to the differential coupling of
where it aids in the appropriate folding of client protein molecules certain mutant JAK2 proteins with cytokine receptors.30 Exon 12
before their trafficking, either to the cell surface or for extracellular mutation K539I has been shown predominantly to bind EPOR,
secretion.12 However, knowledge that c-MPL is an ER client protein whereas JAK2V617F preferentially complexes with MPL.30 Second,
and that CALR mutations were associated exclusively with only ET or homozygosity for JAK2V617F is a key factor in determining the
MF (hence resembling MPL-mutated MPNs) suggested the possibility degree of erythrocytosis that subsequently develops, both in patient
that mutant CALR somehow activates MPL. Consistent with this, samples and animal models.31-33 One can hypothesize that biallelic
mutant CALR can induce an ET/MF phenotype in a variety of mouse expression of JAK2V617F may be required for the mutant protein
models, but only in the presence of MPL.13-17 The mechanism by which to preferentially complex with EPOR, although this is yet to be
mutant CALR complexes with MPL to result in its constitutive activation demonstrated. While clones bearing homozygous JAK2V617F can be
remains unclear. The extracellular domain of MPL, along with both the found as minor subclones in patients with ET, they are clonally
N-terminal and mutant C-terminal of CALR, appear necessary for this dominant in patients with PV.34 The factors that influence the degree
interaction, which may be facilitated by the newly acquired positive of expansion of homozygous JAK2V617F clones are not fully un-
electrostatic charge within the C terminus.13,15 It is unclear why mutant derstood, but the order in which JAK2V617F is acquired relative to
CALR complexes preferentially with MPL and whether mutant CALR– other somatic mutations has been shown to be important.35 Third, patient-
mediated MPL activation occurs after transport from the ER to the cell specific factors, such as iron status, age, sex, coexistent b-thalassemia
surface, or whether aberrant activation occurs intracellularly. traits, and timing of presentation (relative to the disease course in a given
patient), may all influence whether a patient harboring JAK2V617F
Uncommon variants in phenotypic drivers also lead to constitutive presents with significantly elevated red cell parameters and/or throm-
activation of JAK-STAT signaling, such as mutations in exon 12 of bocytosis at diagnosis36 (Figure 2).
JAK2 and the recently identified noncanonical variant MPLS204P.18-20
Occasionally, other proteins that participate in JAK-STAT signaling
(eg, SH2B3 and CBL) are also mutated in MPNs, although they are Genetic interactions influence disease presentation
less frequently found as an isolated somatic mutation in patients.21,22 and progression
Overall, excepting the ~10% of patients with MF or ET who have as-yet Several additional genetic interactions shape the molecular, cellular,
undiscovered drivers of their disease,10 aberrant activation of intracellular and clinical consequences of phenotypic driver mutations in MPN.
signaling via erythropoietin receptor (EPOR) and/or MPL remains
central to the development of the MPN phenotype, regardless of whether Germline predisposition
the phenotypic driver mutation is in JAK2, CALR, or MPL (Figure 1). Constitutional variation that predisposes to MPNs can be classified into
2 groups: (1) common variants, prevalent in the population, that result
in a small predisposition to MPN, and (2) rare variants, often found
Relationship between phenotypic drivers and in familial MPNs, that have a higher penetrance for disease. Well-
clinical presentation recognized examples of the former include the JAK2 46/1 haplotype, as
CALR-mutated ET patients display a phenotype that is remarkably well as single nucleotide polymorphisms in the gene TERT, that confer
similar to those with MPL mutations. Both disease subgroups are an ~1.5- to 3.5-fold increased odds of MPN.37 While up to 10% of
characterized by isolated thrombocytosis and no gender bias at patients are estimated to have additional affected family members, the
presentation.23,24 However, CALR-mutated patients are significantly germline loci responsible for predisposition in familial MPNs have been
younger at presentation than both MPL-mutated and JAK2-mutated ascertained in only a handful of pedigrees.38-41 Two broad mechanisms
counterparts. This is reminiscent of the disease characteristics of PV exist through which germline variation may affect MPN incidence. The
patients with JAK2V617F and JAK2exon12 mutations – those with the observation that JAK2V617F is often found in cis with the 46/1 haplotype
latter exhibit more marked erythrocytosis and present at a younger in heterozygous individuals initially raised the possibility that this allele
age,18 differences which may reflect differential strengths of aberrant was predisposed to acquiring JAK2V617F. However, direct evidence to
signaling via the EPOR. By analogy, one can speculate that CALR support such DNA hypermutability has, thus far, not been demon-
mutations may result in higher levels of MPL signaling compared with strated. An alternative model contends that certain germline genetic

Hematology 2017 471


A B
JAK2 mutaons
JAK2 mutaons CALR and MPL mutaons

MPL
EPOR G-CSFR Mutant
CALR Mutant
MPL MPL
JAK2 JAK2 JAK2 JAK2
JAK2 JAK2
JAK2
JAK2
Mutant JAK2
JAK2

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STATs STATs
MAPK/ERK MAPK/ERK
PI3/AKT ER PI3/AKT

Target genes Target genes

Figure 1. Mutations in JAK2, CALR, and MPL drive excessive myeloproliferation via constitutively active signaling downstream of JAK2. JAK2 associates
with the cytoplasmic portion of a variety of receptors, such as those for erythropoietin (EPOR), thrombopoietin (MPL), and granulocyte/macrophage
colony-stimulating factor (G-CSFR). JAK2 is also activated in response to additional cytokines (eg, growth hormone and IL-5) (not shown). (A) Mutant
JAK2, shown in red, is constitutively active and leads to variable levels of erythroid, megakaryocytic, and, to a lesser degree, granulocytic proliferation and
differentiation. It is unclear whether mutant JAK2 dimerizes with mutant or wild-type JAK2 with respect to the individual receptors. (B) Mutations in CALR
and MPL result in aberrant activation of signaling downstream of the MPL receptor. Mutant CALR complexes with MPL in the ER. Both mutations in
CALR and MPL result in receptor dimerization and activation of JAK2. MAPK/ERK, mitogen-activated protein kinases/extracellular signal-regulated
kinases; PI3/AKT, phosphoinositide 3-kinase/serine/threonine kinase Akt; STAT, signal transducer and activator of transcription.

backgrounds are more permissive for an MPN to emerge. Two recent additional mutations reveal common molecular perturbations, as il-
studies provide evidence for the existence of such an interaction. (1) lustrated in the examples below.
The association between ET and HBS1L-MYB SNP rs9376092 is un-
derstood to be through reduction in MYB expression, which is a recog- Methylation of cytosines at CpG sites is a mechanism through which
nized driver of thrombocytosis.42 (2) Germline duplication of ATG2B information establishing stem cell and differentiation states is retained by
and GSKIP has been shown to enhance sensitivity of megakaryocyte cells following cell division. DNMT3A is a de novo methyltransferase,
progenitors to TPO, particularly in the presence of JAK2V617F, resulting in and TET2, a member of the TET family of proteins, hydroxymethylates
highly penetrant MPNs within certain families.38 Several additional methylcytosines, which may be viewed simplistically as a process of
predisposition loci for MPNs have been recently identified across genes demethylation. Mutations in both genes are prevalent across MPNs,
involved in cell senescence (TERT), JAK-STAT signaling (SH2B3), understood to be loss of function (or dominant-negative effects for
myeloid differentiation (GFI1B), DNA damage and repair (ATM, DNMT3AR882H),45 and result in a hematopoietic stem cell (HSC)
CHEK2), and epigenetic regulation (TET2); this suggests that the germline advantage in murine models.46-49 The similarities in loss-of-function
genetic background of an individual may influence diverse biological consequences despite seemingly opposing functions have recently been
cellular functions to accentuate the molecular and cellular consequences reconciled by work demonstrating that DNMT3A cooperates with
of nascent MPN clones after their acquisition of phenotypic driver TET2 to (1) promote the activity of enhancers important in ensuring
mutations.43 stem cell fitness through the maintenance of high levels of DNA hy-
droxymethylation at enhancer centers50 and (2) repress key lineage-specific
Additional somatic mutations in MPNs transcription factors that promote differentiation in hematopoiesis.51
Approximately one third of patients with MPN have additional mu- Mutations in IDH1/2 also affect DNA methylation via the generation
tations in known drivers of myeloid malignancies. These mutations alter of 2-hydroxyglutarate that competitively inhibits a-KG–dependent DNA
DNA methylation (DNMT3A, TET2, IDH1/2), chromatin modifications hydroxylases, such as TET2 and Jumonji family histone demethylases.52,53
(ASXL1, EZH2, IDH1/2), messenger RNA splicing (U2AF1, SF3B1, Mutant IDH1 has also been linked to increased DNA damage via
SRSF2, ZRSR2), and DNA repair (TP53).10 The presence of certain downregulation of the DNA damage sensor ATM.54 Knock-in mice
mutations, such as in ASXL1, SRSF2, IDH1/2, and EZH2, in patients for IDH1R132H suffer expansion of hematopoietic stem/progenitor cells
with MF is associated with an increased risk of leukemic transformation (HSPCs), extramedullary hematopoiesis, and anemia,55 in keeping with
and/or reduced survival.44 Investigation of the biological effects of these this mutation being found in advanced phases of MPN.

472 American Society of Hematology


Increasing EPO signalling Increasing MPL signalling

Erythrocytosis Thrombocytosis

JAK2Exon 12 JAK2V617F JAK2V617F MPL CALR


homozygosity mutaons mutaons

Addional factors influencing phenotype


Mutaon type
Mutaon homozygosity*
Gender*
Germline predisposion
Addional somac mutaons
Renal funcon/EPO levels*
Iron stores*
Mutaon order*

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Figure 2. Clinical presentation in chronic phase and relationship to phenotypic driver mutation. PV and ET are modeled as a disease spectrum along
a biological continuum where different genetic lesions skew the clinical phenotype from that of thrombocytosis to that of additional erythrocytosis
(6leukocytosis). CALR mutations result in excessive MPL signaling, in a manner similar to that resulting from MPL mutations. JAK2 mutations signal
downstream of multiple cell surface receptors, including MPL, and are thus associated with thrombocytosis but also erythrocytosis and leukocytosis. The
exact nature of the phenotypic driver mutation, germline genetic background, and additional somatic mutations influence disease phenotype. *In the
context of JAK2V617F, several factors modulate the balance between erythrocytosis and thrombocytosis, including sex, mutation homozygosity, and patient-
specific factors such as erythropoietin (EPO) levels, renal function, and iron status.

Perturbation of polycomb repressor complex 2 (PRC2) is another response to the second mutation. Thus, the transcriptional response to
pathogenic mechanism prevalent in MF. EZH2, the enzymatically active TET2 is altered by the presence of a prior JAK2V617F mutation.35 (2) The
subunit of PRC2, compacts chromatin and represses gene transcription first mutation may alter HSC differentiation and give rise to altered target
via histone H3 trimethylation at lysine 27 (H3K27). In myeloid malig- cell populations in which the second mutation can arise. (3) The first
nancies, EZH2 loss-of-function mutations lead to derepression of several mutation may alter the number and function of mature progeny and thus
target genes, such as the Hox gene family, which enhances HSC self- affect the bone marrow microenvironment. Further studies are required
renewal, and Lin28b/ Hmga2, which promotes fibrosis and reduces to address which mechanisms are most important in driving the phe-
erythropoiesis in a JAK2V617F context.56-58 Loss of EZH2 can also be notypic differences in patients with different temporal patterns of
a consequence of other genetic perturbations, such as loss of heterozy- mutation acquisition, and whether phenotype in chronic phase, or
gosity at chromosome 7q, as well as mutations in spliceosome com- disease progression, is influenced by the order of acquisition of other
ponents U2AF1 and SRSF2.59,60 Mutations in ASXL1 are present in up to pairs of common mutations.
a quarter of patients with MF and also lead to reduced PRC2 recruitment,
although other additional pathogenic effects have been reported.61-63 Disease initiation and clonal outgrowth in MPNs
The conventional view of hematopoiesis envisions a self-renewing pool
Order of mutation acquisition of long-term repopulating HSCs producing terminally differentiated
Akin to other cancers, MPNs are clonally heterogeneous, reflecting cells via a series of intermediates. However, recent data from mice
the ongoing interplay between somatic mutation, cellular adaptation to suggest that steady-state hematopoiesis does not routinely rely on HSCs
the changing microenvironment, and selection of tumor subclones. The but predominantly reflects the successive recruitment of thousands of
sequence of acquisition of somatic mutations can be inferred from the transiently active progenitors.65,66 Furthermore, there is now com-
genotypes of detectable subclones. For instance, if some tumor cells pelling evidence for heterogeneity in the differentiation potential of
have JAK2V617F, and others from the same patient bear JAK2V617F with individual cells within the HSC compartment in mice.67-69
an additional somatic mutation, then this indicates that JAK2V617F came
first. Genotyping individual hematopoietic colonies has shown that Direct evidence for a clonal stem-cell origin of MPNs came 40 years ago
the order of acquisition of JAK2V617F, relative to mutations in TET2 or when Adamson and colleagues demonstrated that females with PV who
DNMT3A, influences subclonal composition within HSPCs and mature were heterozygous for 2 glucose-6-phosphate dehydrogenase alleles
cell compartments, disease presentation, and clinical outcome.35,64 In expressed only 1 allele in their blood cells.70 Both JAK2V617F and CALR-
JAK2-first patients, the HSPC compartment is dominated by double- mutated cells are readily detectable in immunophenotypically defined
mutant cells, and such patients present at a younger age, often with PV.35 HSPCs and across all myeloid lineages, confirming that these mutations
Conversely, in TET2-first patients, the HSPC compartment is dominated arise in cells close to the apex of the hematopoietic hierarchy.10,71 It is
by single-mutant cells, and such patients present at an older age, usually tempting to speculate that after the acquisition of a driver mutation,
with ET. Studies of mutation order have also revealed that DNMT3A platelet-biased HSCs might be particularly prone to giving rise to an
mutations, often thought to be early events, frequently occur after an MPN, but direct evidence for this is lacking. In some studies but not
initial JAK2 mutation. This situation is difficult to detect in the absence others, JAK has been found in the lymphoid compartments of patients
of clonal assays because only small numbers of JAK2 single-mutant with MPN, raising the possibility that HSCs with differing degrees of
colonies may be present, probably reflecting their outcompetition by lymphoid potential are targets of somatic mutation in different
double-mutant clones. At least 3 mechanisms, not mutually exclusive, patients.72-76 However, alternative explanations include the presence of
may underlie these observations: (1) The first mutation may alter a cell’s other somatic mutations or the long-lived nature of mature lymphocytes,

Hematology 2017 473


which means it may be many years before an HSC mutation becomes However, studies in mice suggest that although JAK2V617F is capable
detectable in lymphocyte populations. Regardless of the uncertainty over of driving an MPN phenotype, it may be less able to initiate clonal
the precise nature of the cell or cells of origin, for MPNs to emerge expansion in an individual HSC. Three different knockin mouse
requires that (1) these cells acquire phenotypic driver mutations and (2) models have shown that JAK2V617F HSCs are no better or are less
this results in persistent and significant clonal outgrowth. adept than wild-type HSCs in initiating clonal expansion, as assayed
by competitive repopulation transplantation assays.28 Furthermore,
transplantation of single JAK2V617F HSCs into recipient mice only
Acquisition of mutations in hematopoiesis
rarely results in an MPN phenotype.83 Therefore, additional factors
Human cells accumulate somatic mutations throughout their lifetime
may be required for an initiating JAK2 mutation to result in an
as a result of cell-intrinsic mutational processes and exposure to
expanded mutant clone. These may include interaction with the
external mutagens. The accumulated DNA changes in a single cell
constitutional genetic background of a patient or a physiological
can be viewed as a “barcode” that can then be used to estimate tissue-
stochastic expansion of individual HSCs that is independent of the
specific mutation rates, trace the cell’s developmental origins, and
driver mutation. Moreover, there is increasing evidence that aging
understand the nature of DNA-damaging processes. Under normal
and the bone marrow microenvironment may play important roles.
circumstances, these genetic changes are unique to individual cells,
making their study possible only through single-cell interrogation

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Aging is a strong risk factor for MPN. Recent studies demonstrate that
techniques. However, the clonal expansion of tumors renders these
with increasing age, clonal hematopoietic expansions occur in the
aberrations detectable in bulk tissue. Study of these mutation spectra
absence of overt hematological disease.84-87 Mutations leading to clonal
in cancer reveal many mutational patterns, so-called mutation sig-
hematopoiesis (CH) commonly involve DNMT3A, TET2, ASXL1, and
natures, that in turn inform us of the biological processes that drive
PPM1D, but also JAK2V617F. Of note, mutations in CALR have not
mutation acquisition in normal tissues as well as in cancer.77,78
yet been reported in CH. This may reflect the inherent challenges in
detecting such mutations from standard exome sequencing due to
Compared with solid tumors, hematopoietic malignancies are relatively
poor sequencing coverage and alignment efficiency over the mutated
mutation sparse. A key study by Welch and colleagues demonstrated
region. However, it also raises the possibility that CALR mutations have
that the mutation rate in acute myeloid leukemia (AML) was not el-
a higher penetrance for the development of overt disease. Several
evated relative to age-matched hematopoietic progenitors from healthy
observations suggest that CH does not simply reflect the increased risk
individuals, suggesting that most mutations present in AML reflect
of mutation acquisition with age, but that aging itself favors clonal
those acquired before oncogenic transformation.79 Two mutational
expansion. First, CH is rare under the age of 40 years but increases
patterns have been recognized to contribute to background mutation
exponentially in the elderly, a pattern inconsistent with a linear rate of
acquisition in myeloid cells. The first (signature 1) is understood to
somatic mutation accumulation over time.79 Second, some mutations
be the consequence of spontaneous deamination of methylcytosines,
(eg, SF3B1) are associated with CH only in more advanced decades
which results in an age-associated genome-wide accumulation of
of life87; it would be unlikely that specific mutations are acquired at
C.T transition mutations at CpG dinucleotides.77,79 The second pattern
different rates in different age groups. Third, no known oncogenic
of mutations (signature 5) exhibits various nucleotide changes at low
drivers can be identified from analysis of whole-exome or whole-
frequency, but with a bias toward T.C mutations occurring on the
genome sequencing in up to half of individuals with CH, suggesting
transcribed DNA strand.77 The cause of this mutation signature is not
that oncogene-independent mechanisms, such as clonal drift or reduced
known. Both mutational signatures are observed ubiquitously across
bone marrow genetic diversity, can lead to clonal expansion.86,88 It is
somatic tissues as well as in the germline.80
recognized that HSCs undergo a wide range of age-related biochemical
and functional changes, and it seems plausible that some of these may
Whether these background mutational processes are sufficient to
favor the outgrowth of cells that acquire a driver mutation.89 Moreover,
explain the acquisition of specific oncogenic mutations remains the
both cell-intrinsic and environmental influences are likely to play a role.
subject of ongoing research. Two observations suggest that the fre-
quency of acquisition of oncogenic drivers may occur at higher rates
Several lines of evidence point to the importance of environmental
than conventionally thought. First, some patients with MPN have been
effects. Medical interventions, immune dysregulation, and inflammation
shown to harbor multiple oncogenic driver mutations in ancestrally
have all been shown to alter selective pressures for mutant clones within
unrelated clones, suggesting that these mutations can arise multiple
the bone marrow. In TP53-mutated therapy-related MDS, TP53-
independent times in the same individual.81,82 Second, in a recent
mutated cells have been demonstrated to preexist at low levels before
study of familial MPN, two thirds of carriers of a germline duplication
any exposure to therapy but with outgrowth occurring only in the
(involving ATG2B and GSKIP) developed an MPN harboring somatic
context of postchemotherapy bone marrow.90 Furthermore, CH is
mutations in JAK2, CALR, or MPL. The germline duplication enhanced
prevalent in the bone marrow of patients with aplastic anemia, where
the outgrowth of mutant cells, and there was no coexistent evidence of
one can envisage that immune-mediated destruction of normal bone
hypermutability that might otherwise have increased mutation acqui-
marrow cells favors selection for clones more adept at evading cell
sition in these patients.38 Together, these data suggest that acquisition
death, such as those bearing PIG-A mutations, deletion of the major
of phenotypic driver mutations in cells capable of initiating MPNs
histocompatibility locus on chromosome 6p or mutations in TP53-
might be relatively frequent but that clones either remain small (and
inhibitor PPM1D.91 There is also increasing evidence that inflammation
thus are undetected in analyses of cell populations) or do not normally
has a key role in promoting MPN initiation and influencing disease
survive, unless additional conditions facilitate their clonal expansion.
evolution. The secretion of proinflammatory cytokines by bone marrow
stromal cells, such as interleukin-6 (IL-6), IL-33, fibroblast growth
Factors influencing clonal outgrowth of cells with factor, C-X-C motif ligand 10, IL-33, and tumor necrosis factor-a, have
phenotypic driver mutations been shown to preferentially promote the expansion of JAK2V617F-
Approximately half of patients with a JAK2V617F-mutated MPN in mutated clones.92-94 Furthermore, elevated levels of NFE-2 (itself in-
chronic phase lack additional somatic mutations in oncogenic drivers. duced by inflammatory cytokine IL-1b) drive MPN proliferation and

474 American Society of Hematology


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Figure 3. From origins to outcomes. Different evolutionary paths to MPN and disease progression in 4 patients, each with a unique genetic background
(green, gray, red, blue). In the first patient (green), a phenotypic driver mutation acquired in an HSC results in clonal expansion and the emergence of an
MPN phenotype as a consequence of favorable cell-intrinsic and/or environmental factors. The MPN in this context has no additional oncogenic driver
mutations, as is common for patients in chronic phase. Additional driver mutations, such as those that perturb polycomb repressor 2 function (EZH2,
ASXL1 mutations), spliceosome components (SRSF2, SF3B1, U2AF1), or DNA damage repair (TP53), can lead to cells gaining a further clonal
advantage and disease progression. In the second patient (gray), the cell-intrinsic and/or environmental context is not favorable, and a cell acquiring
a phenotypic driver mutation does not have a clonal advantage relative to competing normal cells. In some circumstances, a phenotypic driver mutation
may be insufficient to result in abnormal blood counts and an overt MPN but can instead result in a clonal expansion. Additional mutations or cell-extrinsic
changes may be required to result in emergence of disease (patient in red). Finally, in some patients, phenotypic driver mutations may not be the first event.
Clonal hematopoiesis as a result of mutations in, for example, TET2, DNMT3A, ASXL1 may be the required backdrop for a phenotypic driver mutation to
result in an overt MPN (patient in blue).

progression through modulation of inflammatory cascades, in- Clinical implications and future directions
cluding elevated IL-8 expression.95,96 Overall, it remains unclear The JAK inhibitor ruxolitinib has been a valuable addition to the
exactly how a single phenotypic driver mutation initiates a clonal therapeutic armamentarium for MPNs, in particular for patients with
expansion that will evolve into an overt MPN, but current evidence MF who have splenomegaly and/or disease-related symptoms.97,98
suggests that the constitutional genetic background, aging process, and However, allogeneic stem cell transplantation still remains the only
tumor microenvironment are key factors, with each exerting cell- potentially curative treatment of MPNs, an approach limited by age-
intrinsic and environmental effects (Figure 3). related comorbidities and high treatment-related mortality. Demonstrable

Hematology 2017 475


disease-modifying activity for conventional therapeutic agents is lacking. Acknowledgments
Ruxolitinib and interferon-a have been associated with reductions The authors thank Jacob Grinfeld for valuable comments on the
in allele burdens of phenotypic drivers mutations in some cases, but manuscript.
molecular response is variable and unpredictable. Among the multitude
of novel agents tested in clinical trials, many have shown clinical re- J.N. is supported by a Cancer Research UK Clinician Scientist
sponses but only in a minority of patients, or there are dose-limiting Fellowship and European Haematology Association research award.
toxicities.99 Patient heterogeneity may be a key factor contributing to Work in the Green laboratory is supported by the Wellcome Trust,
the lack of demonstrable clinical efficacy for many agents. Therefore, the Medical Research Council, Bloodwise, Cancer Research UK, and
a major challenge is how we use our emerging understanding of the the National Institute for Health Research Cambridge Biomedical
pathogenetic basis of MPNs to identify groups of patients with shared Research Centre.
disease biology and clinical outcome, such that both existing therapies, as
well as novel agents, can be better targeted to specific patient groups.
Novel paradigms for both disease classification and predictions of Correspondence
clinical outcome may be needed to meet this goal. Anthony R. Green, University of Cambridge Department of Hae-
matology, Cambridge Institute of Medical Research, Hills Rd,

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The 2016 revision to the World Health Organization classification Cambridge CB2 0XY, United Kingdom; e-mail: arg1000@cam.ac.uk.
of MPNs retains the traditional distinction among PV, ET, and MF
and distinguishes between prefibrotic and fibrotic MF.1 However,
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