Page 1260 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 69

ESSENTIAL THROMBOCYTHEMIA

John Mascarenhas, Camelia Iancu-Rubin, Marina Kremyanskaya,
Vesna Najfeld, and Ronald Hoffman

Essential thrombocythemia (ET) is a chronic myeloproliferative haplotype (46/1). The JAK2 46/1 haplotype has been shown not only
neoplasm (MPN) characterized by platelet counts in excess of 450 × to predispose to JAK2V617F-positive ET, but also to ET harboring
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10 /L, profound bone marrow (BM) megakaryocyte hyperplasia, MPL and CALR mutations, again indicating that genetic factors play
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leukocytosis, splenomegaly, a clinical course punctuated by hemor- a role in the susceptibility to develop ET. Tapper and coworkers also
rhagic and/ or thrombotic episodes, and possible evolution to identified an additional two single-nucleotide polymorphisms (SNPs),
myelofibrosis (MF) and acute leukemia. ET is a clinically heteroge- rs12339666 within JAK2 and rs2201862, 153 kb downstream of the
neous disorder, with more than half of patients meeting the criteria DS1 and EVI1 complex locus protein EVI1 (MECOM), which were
for diagnosis being asymptomatic at presentation. ET was first associated with JAK2V617F-negative MPNs. Two additional SNPs,
described in 1934 by Epstein and Goedel, who described a patient rs2736100 in telomerase reverse transcriptase (TERT) and rs9376092
with an elevated platelet count who had repeated hemorrhagic between HBS1L and MYB, were associated with JAK2V617F-positive
episodes. MPNs. The SNP between HBS1L and MYB, rs9376092, however,
had a stronger effect on MPNs associated with CALR and/or MPL
mutations, whereas in JAK2V617F-positive cases rs9376092 was
EPIDEMIOLOGY associated with ET rather than PV. These investigators demonstrated
that the candidate risk allele at rs9376092, which had a strong
The true incidence of ET is unknown because extensive epidemio- association with ET, was associated with reduced MYB. Prior func-
logic studies are not available. The incidence of ET has been estimated tional analyses had shown that mice expressing low levels of MYB
to be approximately 1.5–2.4 patients per 100,000 populations annu- develop a transplantable ET-like disease. These findings indicate that
ally. A Swedish study a indicated that first-degree relatives of patients multiple germ-line variants predispose to the development of each of
with an MPN, including ET, had a five- to sevenfold increased risk the MPNs and link constitutional differences in MYB expression, in
of developing an MPN, supporting the concept that there is a strong particular to ET.
genetic predilection. ET occurs in individuals with a median age of ET has rarely been reported in the pediatric age group. The
67–73 years. To gain additional insight into the patterns of occur- incidence of ET in childhood has been reported to be approximately
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rence of MPNs by age, sex, race/ethnicity, and susceptible popula- 1 per 10 population, which is 60-times less than that in adults.
tions, and provide a population-based assessment of patient survival, Approximately 30% of children with this disorder experience throm-
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Srour and coworkers used data from the Surveillance, Epidemiology botic or hemorrhagic complications at diagnosis or later in their
and End Results (SEER) Program from the National Cancer Institute course, and 50% have splenomegaly. Mutations in one of the estab-
in the United States to better assess the incidence of MPNs in the lished MPN driver genes JAK2, CALR, or MPL were present in a
United States from 2001 to 2012. Importantly, during part of this lower percentage of pediatric cases (34%) compared with adult MPN
period of time the use of mutational analyses in making the diagnosis patients (90%). The subgroup of patients without a detectable driver
of MPNs became widespread. There were 31,904 MPN cases diag- mutation tended to have higher platelet counts compared with
nosed among residents of 18 SEER registries evaluated. The age- patients with mutations.
adjusted incidence rates (IRs) were as follows: polycythemia vera (PV) Several families with multiple members having ET have been
10.9 per 1 million patient years), ET (9.6), chronic myeloid leukemia described. The prevalence of the JAK2V617F mutation in familial
(CML; 3.3), and primary myelofibrosis (PMF; 3.1). ET was the only cases of MPN has been analyzed in 72 families, including 174
MPN with a significantly lower IR among males than females; the patients (68 with ET). The JAK2 mutation was found in half of
average age at diagnosis was 68 years. The female predominance was patients with ET, and a similar proportion as observed in sporadic,
most pronounced in individuals less than 60 years of age. Surpris- nonfamilial cases. Among 46 families with at least two cases of PV,
ingly, the IR of ET was 18% higher among blacks than non-Hispanic ET, or PMF, the JAK2 mutation was absent in six families, heteroge-
whites; ET was associated with a female predominance among non- neously distributed in 18, and present in all patients with MPN in
Hispanic whites, white Hispanics, blacks and Asian–Pacific islanders, 22. Thus, the JAK2 mutation does not seem to be required for the
suggesting shared gender-specific risk factor(s) across these racial/ development of ET or other MPNs, and this familial clustering
ethnic groups. cannot be accounted for by the prevalence of the JAK2 46/1 haplo-
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The incidence patterns observed by Srour and coworkers support type. In familial MPNs, CALR mutations can also be somatically
inherent differences in susceptibility to developing an MPN. This acquired and are associated with an ET or PMF phenotype.
study is of importance, since it represents the first step in appreciating
the potential of molecular diagnostics on improving our understand-
ing of the epidemiology of the MPNs. Future studies will need to PATHOBIOLOGY
include not only JAK2V617F analyses, but also documentation of
mutations in calreticulin (CALR) and the thrombopoietin receptor ET is a clonal hematological malignancy originating at the level of
(MPL). These data suggest that ET is a relatively common hemato- the hematopoietic stem cell. The thrombocytosis that characterizes
logical malignancy that has an especially significant impact on ET is caused by increased platelet production by megakaryocytes.
women. Effective platelet production is increased as much as 10-fold and is
Recently, several groups have identified shared susceptibility genes associated with an increase in megakaryocyte clustering, volume,
that predispose individuals to develop one of the MPNs. The Janus nuclear lobe number, and nuclear ploidy.
kinase 2 (JAK2) mutations (V617F and exon 14 mutations) are not ET is typically a clonal hematopoietic disorder originating at the
acquired randomly, but arise preferentially on a specific JAK2 level of the pluripotent hematopoietic stem cell. A significant

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