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PHYSIOLOGY IN MEDICINE: A SERIES OF ARTICLES LINKING MEDICINE WITH SCIENCE
Physiology in Medicine: Dale J. Benos, PhD, Editor; Edward Abraham, MD, Associate Editor; Peter D. Wagner, MD,
Associate Editor
Annals of Internal Medicine: Harold C. Sox, MD, Series Editor
Narrative Review: Thrombocytosis, Polycythemia Vera, and JAK2
Mutations: The Phenotypic Mimicry of Chronic Myeloproliferation
Jerry L. Spivak, MD
The myeloproliferative disorders polycythemia vera, essential thrombocytosis, and primary myelofibrosis are clonal disorders arising in a
pluripotent hematopoietic stem cell, causing an unregulated increase in the number of erythrocytes, leukocytes, or platelets, alone
or in combination; eventual marrow dominance by the progeny of
the involved stem cell; and a tendency to arterial or venous thrombosis, marrow fibrosis, splenomegaly, or transformation to acute
leukemia, albeit at widely varying frequencies. The discovery of an
activating mutation (V617F) in the gene for JAK2 (Janus kinase 2),
a tyrosine kinase utilized by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these
3 disorders. Constitutive JAK2 activation provides a growth and
survival advantage to the hematopoietic cells of the affected clone.
Because signaling by the mutated kinase utilizes normal pathways,
the result is overproduction of morphologically normal blood cells,
an often indolent course, and (in essential thrombocytosis) usually a
normal life span. Because the erythropoietin, thrombopoietin, and
granulocyte colony-stimulating factor receptors are all constitutively
activated, polycythemia vera is the potential ultimate clinical phenotype of the JAK2 V617F mutation and, as a corollary, is the most
common of the 3 disorders. The number of cells expressing the
JAK2 V617F mutation (the allele burden) seems to correlate with
the clinical phenotype. Preliminary results of clinical trials with
agents that inhibit the mutated kinase indicate a reduction in
splenomegaly and alleviation of night sweats, fatigue, and pruritus.
I
fibrosis, extramedullary hematopoiesis, or transformation
to acute leukemia, albeit at widely varying frequencies.
Moreover, the list of these disorders has grown (Table),
and we now also understand that activating mutations of
many different tyrosine kinases are responsible for
Dameshek’s postulated undiscovered stimulus.
n 1951, William Dameshek (1) hypothesized that such
diseases as polycythemia vera and myelofibrosis with myeloid metaplasia (now designated as primary myelofibrosis),
which he called “myeloproliferative disorders,” might not
be distinct entities but rather interrelated disorders caused
by an as-yet undiscovered stimulus acting on the bone
marrow. Dameshek was prescient in his thinking, because
we now know that the myeloproliferative disorders share
many features, including origin in a pluripotent hematopoietic stem cell; an unregulated increase in the number of
circulating erythrocytes, leukocytes, or platelets, alone or in
combination; clonal dominance (see Glossary); and a tendency to develop arterial or venous thrombosis, marrow
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Key Summary Points . . . . . . . . . . . . . . . . . . . . . . . 301
Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
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Appendix Table
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Ann Intern Med. 2010;152:300-306.
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HEMATOPOIESIS
AND
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CLONALITY
Hematopoiesis is the orderly, continuous process by
which pluripotent hematopoietic stem cells in the marrow
give rise to the cells that populate the blood and lymphatic
systems. Because a single pluripotent hematopoietic stem
cell can give rise to all of the various cell types in the blood
and lymphatic systems, hematopoiesis is by definition a
clonal process (see Glossary). Normally, however, hematopoiesis is polyclonal because several pluripotent hematopoietic stem cells are producing progeny at all times. By
contrast, monoclonality is the hallmark of the myeloproliferative disorders and defines their malignant nature (2).
For unknown reasons, when a pluripotent hematopoietic
stem cell transforms, it gains a survival advantage over its
normal counterparts, such that only the progeny of the
transformed stem cell eventually populate the blood and
marrow. The rate of clonal dominance varies with the par-
Thrombocytosis, Polycythemia Vera, and JAK2 Mutations
Key Summary Points
Polycythemia vera, essential thrombocytosis, and primary
myelofibrosis are hematopoietic stem-cell disorders characterized by clonal dominance and unregulated increase in
circulating erythrocytes, leukocytes, or platelets, alone or
in combination.
Clinical manifestations of these disorders include widely
varying frequencies of arterial and venous thrombosis,
marrow fibrosis, and extramedullary hematopoiesis or
transformation to acute leukemia.
Diagnostic challenges exist because of overlap of clinical
manifestations among these 3 disorders and with other
hematologic disorders, a situation known as phenotypic
mimicry (see Glossary).
Distinguishing these disorders is important because of
differences in natural history, prognosis, and therapy.
Phenotypic mimicry among the chronic myeloproliferative
disorders occurs mainly because of a common mutation
(V617F) in JAK2, the Janus family tyrosine kinase utilized
by the erythropoietin, thrombopoietin, and granulocyte
colony-stimulating factor receptors for ligand-mediated
signal transduction.
The JAK2 V617F mutation results in constitutive activation
of a normal hematopoietic signal transduction pathway
and an exaggeration of normal hematopoiesis modified to
a variable extent by less well-defined genetic and
epigenetic influences.
Polycythemia vera, the most common of the 3 disorders,
differs from its companion disorders because only erythrocytosis occurs in it and diagnosis depends on evidence of
absolute erythrocytosis.
Essential thrombocytosis does not have a unique clinical
phenotype because isolated thrombocytosis can also be
the presenting feature of polycythemia vera or primary
myelofibrosis.
The erythrocytosis present in polycythemia vera is the
ultimate expression of the JAK2 V617F mutation and is
an important therapeutic target.
ticular myeloproliferative disorder, but the reasons for this
are still undefined. For example, characteristically almost
all of the cells in the blood and marrow of patients with
chronic myelogenous leukemia or primary myelofibrosis
are progeny of the malignant clone at diagnosis, whereas in
patients with essential thrombocytosis and polycythemia
vera, blood and marrow cells derived from normal stem
cells are usually present at diagnosis—although clonal
dominance will eventually occur in these disorders as well
(3, 4).
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ACQUIRED JAK2 MUTATIONS
Biology
The genetic lesions responsible for the various myeloproliferative disorders include balanced translocations, deletions, and point mutations, which lead to constitutive
activation of a particular receptor tyrosine kinase in all cases.
These activated kinases not only represent Dameshek’s undiscovered stimulus but also impart the clinical phenotype
(see Glossary) to each myeloproliferative disorder (Table),
permitting for the first time their molecular classification
(5). As shown in the Table, polycythemia vera, essential
thrombocytosis, and primary myelofibrosis are unique
among the myeloproliferative disorders because they share
a mutation causing constitutive activation of JAK2 (Janus
kinase 2 [see Glossary]) and, as a corollary, the interrelatedness that Dameshek predicted (Figure, top). Indeed,
their interrelatedness is epidemiologically unique because
first-degree family members of a patient with 1 of these 3
myeloproliferative disorders have a 3- to 7-fold increased
risk for acquiring any of the 3 disorders (6).
JAK2 is the member of the Janus tyrosine kinase family
that is responsible for signal transduction by the erythropoietin, thrombopoietin, granulocyte macrophage colonystimulating factor, and granulocyte colony-stimulating factor
receptors in hematopoietic cells, as well as for signal transduction by many cytokine receptors, such as interleukin (IL)-3,
IL-5, and IL-6 receptors (7). JAK2 is normally activated
when these receptors bind their cognate ligands (see
Glossary): erythropoietin, thrombopoietin, granulocyte
colony-stimulating factor, granulocyte macrophage colonystimulating factor, IL-3, IL-5, or IL-6. However, in the myeloproliferative disorders, a point mutation resulting in a
switch from phenylalanine to valine at amino acid position
671 (V617F) in the regulatory domain of the protein releases
the adjacent kinase domain from inhibition, leading to constitutive activation in the absence of any ligand (8). The activated kinase promotes cell proliferation and resistance to cell
Table. The Chronic Myeloproliferative Disorders
Disease
Molecular Defect*
Chronic myelogenous leukemia
Chronic eosinophilic leukemia and the
hypereosinophilic syndrome
Chronic neutrophilic leukemia
Chronic myelomonocytic leukemia
Systemic mastocytosis
Polycythemia vera
BCR-ABL
FIP1L1-PDGFRA
Essential thrombocytosis
Primary myelofibrosis
BCR-ABL p230
TEL-PDGFRB
KIT D816V
JAK2 V617F (⬃92% positive)
JAK2 exon 12 mutations (3%
positive)
JAK2 V617F (⬃50% positive)
MPL W515L/K (⬃3% positive)
MPL K39N
JAK2 V617F (⬃50% positive)
MPL W515L/K (⬃14% positive)
* Representative molecular defects caused by balanced translocations or point mutations in the chronic myeloproliferative disorders.
2 March 2010 Annals of Internal Medicine Volume 152 • Number 5 301
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Thrombocytosis, Polycythemia Vera, and JAK2 Mutations
Figure. The close interrelationship among the chronic
myeloproliferative disorders, and a schematic representation
of hematopoietic stem-cell commitment and JAK2
utilization.
The Interrelationship Among the
Chronic Myeloproliferative Disorders
Primary Myelofibrosis
Isolated
Thrombocytosis
Polycythemia Vera
Essential Thrombocytosis
Schematic Representation of the Progenitor Cells
Most Sensitive to JAK2 V617F
Pluripotent
Hematopoietic
Stem Cell
Common
Lymphoid
Progenitor Cell
Epidemiology
Common
Myeloid
Progenitor Cell
T Lymphocytes
B Lymphocytes
Granulocyte-Monocyte
Progenitors
fect is most pronounced in maturing hematopoietic cells,
which require erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor for proliferation and survival, compared with undifferentiated hematopoietic stem
cells, which do not (9) and in which only the thrombopoietin receptor is expressed (10). Of importance, unlike most
of the other disorders in the Table, with JAK2 mutations,
constitutive signaling still occurs through normal signal
transduction pathways. Consequently, the result is overproduction of morphologically normal blood cells, a generally indolent course, and in essential thrombocytosis usually a normal life span (11).
JAK2 V617F is probably not the initiating molecular
defect in polycythemia vera, essential thrombocytosis, or
primary myelofibrosis, because it is not present in all patients (12), particularly those with the familial form of
these disorders (13); it can be acquired by the malignant
clone after the acquisition of other genetic abnormalities
(14, 15); and it is also absent in the myeloblasts of some
patients expressing JAK2 V617F in their mature blood cells
when leukemic transformation occurs (16). In addition, in
contrast to JAK2 V617F, which is located in exon 14 of the
gene, several different activating mutations have also been
identified in exon 12 (17), which, for unknown reasons,
primarily cause erythrocytosis but occasionally may be associated with thrombocytosis and splenomegaly (18).
Erythroid Progenitors
JAK2 V617F
Megakaryocyte
Progenitors
Top. The chronic myeloproliferative disorders not only are phenotypically similar but can also evolve into each other. From a clinical perspective, as illustrated isolated thrombocytosis of unknown cause should not
automatically be assumed to be essential thrombocytosis because isolated
thrombocytosis can also be the presenting manifestation of polycythemia
vera or primary myelofibrosis. Bottom. JAK2 is an obligatory kinase
primarily for erythroid and megakaryocytic cell development; granulocytes can also use JAK1, and lymphocytes do not require JAK2. As
illustrated, polycythemia vera is the ultimate clinical phenotype that can
be caused by constitutive JAK2 activation.
death, as well as hypersensitivity to hematopoietic growth factors and cytokines signaling through receptors utilizing JAK2.
Thus, cells expressing the mutant JAK2 have both a
growth and a survival advantage over their normal counterparts and expand their numbers autonomously. This ef302 2 March 2010 Annals of Internal Medicine Volume 152 • Number 5
JAK2 V617F expression is present in more than 95%
of patients with polycythemia vera and in approximately
50% of patients with essential thrombocytosis and primary
myelofibrosis (19 –23). The various mutations in JAK2
exon 12 account for the disease in an additional 3% of
patients with polycythemia vera (17, 18, 24). In a small
proportion of patients with essential thrombocytosis and
primary myelofibrosis, mutations are present in the thrombopoietin receptor gene MPL (18, 25, 26), but the genetic
basis for these disorders in other patients is still unknown.
JAK2 V617F expression has also been observed at a very
low frequency in various other clonal myeloid disorders
(24, 27, 28), but with the exception of a subgroup of
patients with sideroblastic anemia and thrombocytosis
(29), none display elements of the clinical phenotype associated with JAK2 V617F expression in polycythemia vera,
essential thrombocytosis, or primary myelofibrosis.
How the same mutation could be responsible for 3
different clinical phenotypes is not entirely known. In vitro
clonal assays (30), animal models (31, 32), studies quantitating the JAK2 V617F allele burden in humans (see Glossary) (12, 33, 34), and the recent identification of a characteristic constitutional JAK2 haplotype (see Glossary) in
patients with a myeloproliferative disorder (35–37) and
other mutated genes (such as TET2 [38]) indicate that
gene dose, sex, genetic predisposition, and additional mutations all have roles. With respect to gene dose, the JAK2
V617F allelic burden correlates with clinical phenotype in
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Thrombocytosis, Polycythemia Vera, and JAK2 Mutations
the myeloproliferative disorders. In essential thrombocytosis, where the JAK2 V617F allele burden is usually low
(12), thrombocytosis alone is the rule, the JAK2 V617F
allelic burden is relatively constant, and homozygosity for
the mutation is infrequent (4, 39). In polycythemia vera,
however, because of a propensity for mitotic recombination (see Glossary) involving chromosome 9p, where the
JAK2 gene is located (40), the incidence of homozygosity
for the mutation increases during the disease (12), and the
increased JAK2 V617F allelic burden is associated with
erythrocytosis, leukocytosis, splenomegaly, and pruritus in
addition to thrombocytosis (41).
Pathophysiology
Because JAK2 is the obligate tyrosine kinase for the
erythropoietin and thrombopoietin receptors (the granulocyte colony-stimulating factor receptor can also utilize
JAK1), polycythemia vera is the ultimate phenotypic expression of JAK2 V617F (Figure, bottom). In this regard,
many patients with polycythemia vera present initially
with thrombocytosis alone, which is well documented
(42). Furthermore, many JAK2 V617F–positive patients
with essential thrombocytosis have a “polycythemia vera–like”
phenotype compared with their JAK2 V617F–negative
counterparts, with relatively higher hematocrits and leukocyte counts and an increased incidence of venous thrombosis (43). Indeed, when the erythrocyte mass was measured directly in such patients, approximately 65% of
them actually had absolute erythrocytosis (see Glossary)
and thus had unrecognized polycythemia vera (44), supporting the proposition that polycythemia vera is the
ultimate phenotypic expression of JAK2 V617F and
should always be considered in the differential diagnosis
of isolated thrombocytosis.
The reason for the masked erythrocytosis in JAK2
V617F–positive patients with apparent essential thrombocytosis can be explained as follows. An increase in erythrocyte production (Appendix Table, available at www.annals
.org) due to recombinant erythropoietin (45), chronic
carbon monoxide exposure (46), or androgenic steroids is
associated with a reciprocal decrease in the plasma volume
because the body always attempts to maintain a normal
total blood volume. By contrast, for unknown reasons, in
polycythemia vera, where endogenous erythropoietin production is suppressed, the plasma volume either does not
change or increases with expansion of the erythrocyte mass
(47, 48). This initially has the beneficial effect of reducing
peripheral vascular resistance, but at the same time it can
mask the actual increase in the erythrocyte mass, resulting
in an apparently normal hematocrit. The situation is exacerbated with splenomegaly, because the plasma volume will
expand even further (47). Unfortunately, the expanded
plasma volume is not protective against venous or arterial
thrombosis, which are the most common causes of morbidity and mortality in polycythemia vera (49).
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Of course, conditions that solely contract the plasma
volume (Appendix Table) will also make the hematocrit or
hemoglobin level seem elevated when it is not. These observations have important clinical ramifications: A high hematocrit or hemoglobin level is not synonymous with true
erythrocytosis any more than a normal hematocrit or hemoglobin level is synonymous with the absence of erythrocytosis when polycythemia vera is a diagnostic consideration (44, 47, 48). Indeed, unless the hematocrit is 60% or
greater (hemoglobin level, 20 g/dL), distinguishing plasma
volume contraction from absolute erythrocytosis is not
possible (50).
HOW IS THE JAK2 V617 ASSAY USED
DIAGNOSTICALLY?
The Differential Diagnosis of Thrombocytosis and
Polycythemia Vera
The discovery of JAK2 V617F provided a way to distinguish polycythemia vera and approximately 50% of patients with essential thrombocytosis and primary
myelofibrosis, from the many benign and malignant disorders they mimic clinically, albeit not from each other (51).
Thus, the presence of the JAK2 V617F mutation confirms
the clinical impression of a myeloproliferative disorder, but
because the mutation occurs in all 3 disorders, it cannot be
used to distinguish among them, nor does its absence exclude a myeloproliferative disorder. However, because
polycythemia vera is the ultimate clinical phenotype of
JAK2 V617F expression and the most common myeloproliferative disorder, a positive JAK2 V617F assay should always suggest the possibility of this disorder.
Because only erythrocytosis distinguishes polycythemia vera from essential thrombocytosis and primary
myelofibrosis, the diagnosis of polycythemia vera is still
clinically based. At the same time, although polycythemia
vera is the ultimate expression of a JAK2 mutation, not all
patients with erythrocytosis expressing a JAK2 mutation
will develop polycythemia vera (18). With expanded access
to medical care, patients with myeloproliferative disorders
are being seen much earlier in the course of their disease,
and the marked degree of hematocrit or hemoglobin elevation classically associated with polycythemia vera is no
longer commonly encountered. Thus, the presence of polycythemia vera may only become apparent over time.
When polycythemia vera presents with erythrocytosis,
often microcytic; leukocytosis; and thrombocytosis, the diagnosis is not in doubt. This is also true when it presents as
erythrocytosis together with thrombocytosis or leukocytosis or splenomegaly (52). Furthermore, tissue iron deficiency is often paradoxically associated with erythrocytosis
in polycythemia vera because of iron utilization by the
expanding the erythrocyte mass, which could, of course,
contribute to the presence of thrombocytosis (53). However, between 7% and 20% of patients with polycythemia
vera present initially with only thrombocytosis (4, 42) and
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Thrombocytosis, Polycythemia Vera, and JAK2 Mutations
up to 17% with only erythrocytosis (54). A JAK2 V617F
assay can be useful diagnostically in these patients. With
respect to diagnostic parsimony, however, although polycythemia vera is the most common myeloproliferative disorder, investigators of a large epidemiologic study found
that only 5% of patients with persistent erythrocytosis had
polycythemia vera (52). Therefore, the first obligation
when presented with a patient with a persistent high hematocrit or hemoglobin level is not to look for polycythemia vera but rather to look for correctable causes of erythrocytosis (Appendix Table).
In a patient suspected of having erythrocytosis, a careful history with respect to tobacco (46) or androgen (55)
use or a sleep disturbance (56) combined with arterial oxygen saturation and serum erythropoietin measurements
constitute the initial evaluation. A low or normal serum
erythropoietin level is an indication for a JAK2 V617F
assay, because a low serum erythropoietin level indicates
that the marrow erythroid progenitor cell pool has probably expanded autonomously, and a normal serum erythropoietin level provides no diagnostic clues. If the serum
erythropoietin level is high, a secondary form of erythrocytosis may be present. If a JAK2 V617F assay is negative and
tobacco use, sleep apnea, or hepatic or renal abnormality is
not evident, hematologic referral is indicated for evaluation
of mutations involving JAK2 exon 12 (18), the von
Hippel–Lindau gene (Chuvash polycythemia) (57), the
erythropoietin receptor, or hemoglobin genes (58).
ARE JAK2 MUTATIONS RELEVANT TARGETS
THERAPY?
FOR
DRUG
Management of the Chronic Myeloproliferative
Disorders
JAK2 is an obligatory kinase for the proliferation and
differentiation of erythroid cells and megakaryocytes and,
therefore, is a relevant therapeutic target for agents that
specifically inhibit its activity. To date, clinical trials are
investigating several JAK2 inhibitors in patients with myeloproliferative disorder, and more inhibitors are being developed (59, 60). The results to date indicate that these
inhibitors reduce splenomegaly and alleviate constitutional
symptoms, such as night sweats, fatigue, and pruritus, in a
reversible manner, suggesting that a substantial inflammatory component contributes to the signs and symptoms of
the myeloproliferative disorders (61), possibly through
JAK2 V617F–activated cytokine receptors. However, these
inhibitors have had only a modest impact on the JAK2
V617F allele burden, although this may require a longer
duration of therapy. At the same time, pluripotent hematopoietic stem cells do not seem to require JAK2 for their
survival or proliferation (9), and JAK2 mutations, unlike
the BCR-ABL fusion kinase in chronic myelogenous leukemia, are probably not the initiating molecular event in
polycythemia vera, essential thrombocytosis, or primary
myelofibrosis. Therefore, JAK2 inhibitors may prove to be
304 2 March 2010 Annals of Internal Medicine Volume 152 • Number 5
Glossary
Absolute erythrocytosis: An elevated hematocrit or hemoglobin level can be
caused by an elevated erythrocyte mass (absolute erythrocytosis) or a
contracted plasma volume (pseudo- or relative erythrocytosis).
Allele: Each one of a pair of chromosomes has a single copy of a particular
gene located at the same position. These copies are known as the alleles
of the gene. The copies may be identical (homozygous) or may differ
(heterozygous) with respect to their DNA composition, such as when 1
allele has a mutation or single nucleotide polymorphism.
Allele burden: The percentage of cells expressing a mutation in 1 or both
alleles of a gene. For the JAK2 V617F mutation on chromosome 9p, the
allele burden is usually measured in the blood neutrophils. The allele
burden provides an estimate of the number of neutrophils from the
malignant clone present in the circulation and thus whether clonal
dominance is present. However, unless the allele burden is greater than
75%, it cannot provide an estimate of whether 1 or both JAK2 alleles are
involved. For example, a neutrophil JAK2 V617F allele burden of 50%
could indicate that all of the circulating neutrophils are derived from the
malignant clone but have only 1 allele involved (heterozygosity for the
mutation) or that 50% of the neutrophils have both JAK2 alleles mutated
(homozygosity for the mutation) but 50% are from normal clones and
have no mutated alleles. The marrow neutrophil allele burden is similar to
the blood neutrophil allele burden.
Clonal dominance: This occurs when the cells from 1 clone in a cell
population have a growth advantage over the cells from all of the other
clones. Usually in hematopoietic malignant conditions, such as acute
leukemia or chronic myelogenous leukemia, there is clonal dominance by
the malignant clone at disease presentation. In the chronic
myeloproliferative disorders, this is usually also true for primary
myelofibrosis but not for polycythemia vera or essential thrombocytosis, in
keeping with their more indolent clinical course.
Clonality: This describes the stem-cell origin of a cell population. If all of the
cells are derived from the same parental stem cell, the cell population is
monoclonal. If the cells arise from several different parental stem cells, the
cell population is polyclonal, which is the normal situation.
Cognate ligand: A protein that specifically binds to and activates a particular
cell surface receptor. For example, erythropoietin is the cognate ligand of
the erythropoietin receptor.
Genotype: The full complement of inherited genetic information in a person,
but the term is also used to refer to the allelic status of a specific gene or
single nucleotide polymorphism.
Haplotype: The alleles at various loci on a chromosome that are transmitted
together. Alternatively, the term is used to refer to a set of single
nucleotide polymorphisms that are statistically associated on the same
chromosome.
Janus kinases: A tyrosine kinase family comprising 4 members, JAK1, JAK2,
JAK3, and TYK2, which are utilized by hematopoietic growth factor and
cytokine receptors to phosphorylate tyrosine residues on specific
intracellular proteins after the interaction of the receptor with its ligand.
JAK2 is used by the erythropoietin, thrombopoietin, and granulocyte
colony-stimulating factor receptors to transmit signals and thus is
integrally involved in hematopoiesis. JAK1, JAK3, and TYK2 are used by
the interleukin and interferon receptors to transmit signals and thus are
primarily involved in the regulation of immune function.
Phenotype: The observed physical and behavioral characteristics of an
organism or a disease.
Phenotypic mimicry: When the clinical features of 2 diseases are similar but
their genotypes differ.
Mitotic recombination: When chromatids exchange genetic material during
mitosis, the resulting chromosome pairs will share identical alleles in the
region that the crossover occurred, resulting in loss of the expected
heterozygosity of those alleles. Mitotic recombination is the genetic
mechanism thought to account for homozygosity with respect to the JAK2
V617F mutation on chromosome 9p. Loss of heterozygosity is an important
mechanism by which tumor cells gain advantage over normal cells.
Single nucleotide polymorphism: A DNA sequence variation occurring when
a single nucleotide—A, T, G, or C—differs between paired chromosomes
because of a nucleotide substitution, deletion, or insertion that produces 2
alleles. These can occur anywhere in a gene and may be silent or may
cause an alteration in gene function or expression. Because nearby single
nucleotide polymorphisms on a chromosome often closely correlate,
analysis can be used to identify specific regions of the genome and also
the extent to which different persons share the same sequence of alleles
(haplotype) in that particular genomic region.
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Thrombocytosis, Polycythemia Vera, and JAK2 Mutations
useful only for suppressing disease manifestations but not
for eradicating disease, in contrast to such agents as interferon (62), which seem capable of eradicating the malignant clone (63). Of course, none of these agents can substitute initially for phlebotomy therapy for polycythemia
vera, which immediately reduces the erythrocyte mass and
lowers blood viscosity (64).
From the Johns Hopkins Medical Institutions, Baltimore, Maryland.
Grant Support: From the National Institutes of Health (P01CA108671).
Potential Conflicts of Interest: Disclosures can be viewed at www
.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum⫽M09
-1012.
Requests for Single Reprints: Jerry L. Spivak, MD, Hematology Division, Johns Hopkins University School of Medicine, Traylor Building,
Room 924, 720 Rutland Avenue, Baltimore, MD 21205-2196; e-mail,
[email protected].
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Annals of Internal Medicine
Appendix Table. Causes of Absolute Erythrocytosis and
Relative Erythrocytosis
Causes of absolute erythrocytosis
Hypoxia
High-affinity hemoglobins
High altitude
Pulmonary disease
Right-to-left shunts
Sleep apnea
Neurologic disease
Renal disease
Renal artery stenosis
Focal sclerosing or membranous glomerulonephritis
Renal transplantation
Tumors
Hypernephroma
Hepatoma
Cerebellar hemangioblastoma
Uterine fibromyoma
Adrenal tumors
Meningioma
Pheochromocytoma
Drugs
Androgenic steroids
Recombinant erythropoietin
Familial (with normal hemoglobin function)
Chuvash ethnicity
Erythropoietin-receptor mutations
2,3-Bisphosphoglycerate deficiency
Polycythemia vera
JAK2 V617F
JAK2 exon 12 mutations
Causes of relative erythrocytosis
Loss of fluid from the vascular space
Emesis
Diarrhea
Diuretics
Sweating
Polyuria
Hypodipsia
Hypoalbuminemia
Capillary leak syndromes
Burns
Peritonitis
Chronic plasma volume contraction
Hypoxia from any cause
Androgen therapy
Recombinant erythropoietin therapy
Hypertension
Tobacco use
Pheochromocytoma
Ethanol abuse
Sleep apnea
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2 March 2010 Annals of Internal Medicine Volume 152 • Number 5 W-95