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CHAPTER 85 studies suggest a familial tendency to develop MPNs, including ET.
6,7
This predisposition appears to be explained in part by inheritance of a
ESSENTIAL specific haplotype that contains the Janus family of tyrosine kinases type
2 (JAK2) gene.
8
THROMBOCYTHEMIA PATHOGENESIS

ET is characterized by hyperactive cytokine signaling which in 50 to
Philip A. Beer and Anthony R. Green 60 percent of cases is the result of somatic mutations targeting
components of signaling pathways, including the JAK2 gene or the
thrombopoietin receptor gene (MPL). Mutations in calreticulin gene
SUMMARY (CALR) are present in the majority of JAK2/MPL–wild-type patients,
leaving approximately 10 percent of ET patients without a mutation in
any of these genes (JAK2/MPL/CALR–wild-type or “triple-negative”
Essential thrombocythemia is a clonal stem cell disorder characterized by an patients). A minority of ET patients also harbor mutations in transcrip-
overproduction of platelets and associated with mutations in the JAK2, CALR, or tional regulation pathways (Fig. 85–1).
MPL gene. Complications include thrombosis (predominantly arterial), hemor- A JAK2 V617F mutation is found in approximately 50 percent of
rhage, and progression to myelofibrosis or acute myeloid leukemia. Diagnosis patients with ET. JAK2, a cytoplasmic tyrosine kinase, forms a com-
9
requires exclusion of reactive thrombocytosis and other myeloid malignancies plex with and is essential for signaling by the erythropoietin and
associated with a raised platelet count. Therapy is aimed at reducing throm- thrombopoietin receptors 10,11 ; JAK2 also contributes to signaling by
botic complications and includes modification of known cardiovascular risk the granulocyte colony-stimulating factor, granulocyte-macrophage
12
factors and antiplatelet therapy for the majority of patients. Those at high risk colony-stimulating factor, and interferon-γ receptors. Cytokine bind-
of thrombosis are also considered for cytoreductive therapy with agents such ing leads to a conformational change in the JAK2-receptor complex,
as hydroxyurea, anagrelide or interferon-α. Although the majority of patients with consequent activation of JAK2 kinase activity and recruitment of
V617F
10,13,14
can expect to live for many years, mortality rates are increased compared to downstream signaling pathways. The JAK2 mutation alters a
critical residue within the autoinhibitory pseudokinase (JH2) domain,
the general population as a consequence of disease complications.
resulting in increased JAK2 basal kinase and downstream signaling
activity. The cellular consequences of mutant JAK2 expression include
15
increased proliferation, cytokine hypersensitivity, cytokine-independent
differentiation, and inhibition of apoptosis. The central role of JAK2
9
DEFINITION AND HISTORY in erythropoiesis is highlighted by a JAK2 knockout mouse, which
dies in midgestation from severe anemia. In addition, mice engi-
12
Essential thrombocythemia (ET), one of the myeloproliferative neo- neered to express the JAK2 V617F allele recapitulate features of human
plasms (MPNs), is a clonal hematopoietic stem cell disorder char- ET or PV. 16
acterized by thrombocytosis and associated with thrombotic and Acquired mutations in MPL are found in 4 percent of ET patients,
hemorrhagic complications. First recognized as a specific disease entity the majority of whom are JAK2–wild-type, and a similar proportion of
in 1934 and as a clonal disorder in 1981, ET shares clinical and patho- those with PMF, but not in patients with PV. 17,18 These mutations alter
2
1
logic similarities with other MPNs, particularly polycythemia vera (PV) residues in the juxtamembrane (MPL W515 ) or transmembrane (MPL S505N )
and primary myelofibrosis (PMF). regions and lead to constitutive activation of the receptor complex. 19,20
Expression of the MPL W515L allele in a mouse model recapitulated fea-
EPIDEMIOLOGY tures of human ET and PMF. Occasional patients with ET, as well
21
as PV and PMF, harbor loss of function mutations in SH2B3 which
The annual incidence of ET is in the order of 1 to 2.5 per 100,000 per encodes LNK, an important negative regulator of JAK/STAT (signal
population and appears slightly more common in females. Patients transducer and activator of transcription) signaling. 22
3,4
may present at any age, although ET is largely a disorder of later life with The majority of ET patients without a signaling pathway mutation
a peak incidence between the ages of 50 and 70 years. Presentation in harbor a somatic mutation in CALR (encoding calreticulin). CALR
childhood is rare but well recognized. mutations are found in 15 to 35 percent of ET patients and a similar pro-
portion of those with PMF but not in PV. Calreticulin is a key endoplas-
ETIOLOGY mic reticulum protein with calcium buffering and protein chaperone
23
Little is known about the precise etiology of this disorder, although activity. Although CALR-mutant patients generally lack mutations in
environmental factors such as exposure to radiation have been impli- JAK2 or MPL, they nonetheless show signaling pathway activation, sug-
cated in the genesis of other MPNs. Both registry data and kindred gesting an as yet undetermined role for CALR in cytokine signaling. 24–26
5
Mutations targeting pathways implicated in the control of gene
transcription are found in a minority of patients with ET, as well as those
with PV, PMF and other myeloid neoplasms (see Fig. 85–1B). These
Acronyms and Abbreviations: AML, acute myeloid leukemia; CALR, calreticulin mutations, which may coexist with mutations in JAK2, MPL, or CALR,
gene; CML, chronic myeloid leukemia; ET, essential thrombocythemia; JAK2, Janus target genes involved in DNA methylation (TET2, IDH1/2, DNMT3A),
27
family of tyrosine kinases type 2; MPL, the thrombopoietin receptor; MPN, myelopro- histone modification (EZH2) or RNA splicing (SF3B1). In addition to
liferative neoplasm; PCR, polymerase chain reaction; PMF, primary myelofibrosis; PV, its roles in cytokine signaling, JAK2 has also been shown to translo-
polycythemia vera; RARS-T, refractory anemia with ringed sideroblasts and thrombo- cate to the nucleus where it acts as a mediator of gene transcription
cytosis; STAT, signal transducer and activator of transcription. through the direct modification of histone proteins. Whereas nuclear
translocation of wild-type JAK2 appears to be activation-dependent,

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