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1292 Part X: Malignant Myeloid Diseases Chapter 84: Polycythemia Vera 1293

of clonal hematopoiesis. Once large enough, the clone then suppresses hemoglobin, and differences in marrow morphology. Disease course
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and replaces normal polyclonal hematopoiesis. The clonal origin of PV and clinical outcome, however, are similar. 46
has been demonstrated in women heterozygous for a polymorphic Studies of families of MPN patients, in which several different
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X-chromosome marker such as, glucose-6-phosphate dehydrogenase MPNs occur in a single pedigree, indicate that JAK2 mutations may
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as well as by more modern clonality assays (Chap. 10). In both cases, all not be solely responsible for the disease phenotype and may not even
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hematopoietic cell lineages express either one isoform of the enzyme, represent the disease-initiating event. A number of compelling lines
or some polymorphic allele encoded by the maternal or paternal X of evidence support this conclusion. First, in familial PV, there is no
chromosome, whereas T lymphocytes and nonhematopoietic cells are clear linkage between the disease and chromosome 9p, the genetic
a mosaic of both enzyme types. site of JAK2, suggesting an independent germline predisposition to
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In vitro marrow- or blood-derived erythroid colonies of PV PV. Second, in familial PV, affected members can be either JAK2 V617F -
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patients arise from both normal burst-forming unit–erythroid (BFU-E) positive or -negative. Third, acquisition of the JAK2 V617F mutation may
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precursors and BFU-E precursors that are erythropoietin-independent. be a late genetic event. Fourth, in sporadic PV, only a proportion of
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Erythropoietin-independent BFU-E precursors form so-called endoge- clonal PV cells are JAK2 V617F -positive. And fifth, acute leukemic trans-
nous erythroid colonies (EECs), 15–18 a characteristic feature of PV. The formation of any JAK2-positive MPN, including PV, is frequently nega-
fibroblasts that accumulate in the marrow of patients with PV as the tive for the JAK2 V617F mutation. 35,50 These diverse observations strongly
disease progresses are not part of the abnormal PV clone. Rather, they suggest that the somatic mutation of the JAK2 gene is not the initiat-
seem to accumulate in response to cytokines released by megakaryo- ing or sole pathogenic process in PV, but in most patients is essential
cytes and other cells (Chap. 86). 19 for the clinical phenotype of PV. The pathways leading to acquisition
Other abnormalities that have been described include decreased of the JAK2 V617F mutation, homozygosity of JAK2 V617F , and participation
levels of a platelet thrombopoietin receptor, deregulation of bcl-x, of many other genes in the 9p UPD region may have phenotypic and
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an inhibitor of apoptosis, increased expression of protein tyrosine prognostic significance. 51,52 Additional prognostic significance can be
phosphatase activity by red cell precursors, and acquired loss-of- ascertained by analysis for clustering of specific genes. 53
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heterozygosity of chromosome 9p as a result of uniparental disomy A genomic chromosome 9p functional variant might also be rel-
(UPD). This last observation was one of two routes that led to the dis- evant to the pathogenesis of JAK2 V617F . Independent occurrence of the
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covery of the JAK2 2343G > T mutation encoding the V617F mutation JAK2 V617F mutation on different haplotypes was found, although a spe-
located on chromosome 9p, 12,23 which has improved our understanding cific constitutional inherited JAK2 haplotype (GGCC, 46/1), associated
of disease pathogenesis, improved the specificity of diagnosis, and led with the JAK2 V617F somatic mutation, was found in most JAK2 V617F -
to an explosion of research in MPN (see “JAK2 V617F Mutation” below). positive individuals. The risk of acquiring a JAK2 V617F -positive MPN is
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There are no specific karyotypic markers occurring with high three to four fold higher in patients with the JAK2 GGCC (46/1) hap-
frequency in PV. Fewer than 25 percent of patients have karyotypic lotype. 54–57 This GGCC haplotype of JAK2 also confers susceptibility to
abnormalities at diagnosis, 24–29 but the incidence rises with the increas- JAK2 exon 12 mutation-positive PV. These studies suggest that pre-
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ing duration of the disease, 25,30 suggesting that karyotypic abnormali- JAK2 hypermutability events exist and that germline genetics play an
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ties represent secondary genetic events. Cytogenetic abnormalities important role in the early pathogenesis of MPNs.
may potentially herald transformation from PV to myelofibrosis, acute
myeloid leukemia, or a myelodysplastic syndrome, but as of now, these OTHER MUTATIONS
associations are weak. 29 In addition to the important role of JAK2 V617F and other JAK2 mutations
in the etiology of PV and other MPNs, mutations in other genes may be
JAK2 V617F MUTATION important to the full genesis of these disorders.
TET2 is a homologue of the gene originally discovered at the chro-
JAK2 kinase is present in all hematopoietic cells and is essential for pro- mosome ten-eleven translocation (TET) site in a subset of patients with
liferative intracellular signaling in response to a variety of hematopoi- acute leukemia. TET2 mutations were found in hematopoietic cells
etic growth factors (Chaps. 34 and 57). The V617F mutation was first from a significant proportion of patients with PV and other MPNs. 58,59 It
identified in PV in 2004, and was simultaneously reported by several has been established that TET2 loss-of-function mutations originate in
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laboratories. 32–34 The V617F mutation is present in virtually all patients pluripotent hematopoietic stem cells but seem to favor myeloid rather
with PV and in more than 50 percent of patients with essential throm- than lymphoid proliferation, and that in many patients both TET2 alle-
bocytosis (ET; Chap. 85) and myelofibrosis (MF; Chap. 86); rarely is les were affected. However, studies in familial PV demonstrated that
it found in the minority of patients with other myeloproliferative dis- the TET2 mutation is often not disease-initiating, as the TET2 muta-
orders. 35,36 In PV (unlike in ET), it is often in its associated homozy- tions differ among affected relatives and, in some instances, the TET2
gous form as a result of UPD, at least in some of the progenitors. 26,37 mutations followed, rather than preceded, the appearance of JAK2 V617F 60
.
Patients bearing homozygous JAK2 V617F tend to have a longer duration Additionally, recurrent TET2 mutations have been reported in elderly
of disease, higher hemoglobin levels, and increased incidence of pru- patients with clonal hematopoiesis but no evidence of hematological
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ritus and are more likely to transform to post-PV MF (Chap. 86). malignancy. Several additional genes commonly bear mutations in PV
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The JAK2 V617F allele burden in PV may also be correlated with increased patients, including ASXL1, DNMT3A, and IDH1/2. 62,63 The quantitative
spleen volume, increased leukocytosis, and severity of MF. 39–42 It should proportion of clones carrying different mutations may change during
be noted, however, that PV patients can achieve a complete hemato- disease progression. 64
logic remission without a significant molecular response (i.e., a decrease
in JAK2 V617F allele burden). In some of the rare PV patients who are AUTOIMMUNITY AND CHRONIC
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JAK2 V617F -negative, a different JAK2 mutation is present in exon 12.
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Several different JAK2 exon 12 mutations, including missense muta- INFLAMMATION
tions, insertions, and deletions, have been described. Patients with exon Although JAK2 kinase is clearly involved in the pathogenesis of PV,
12 mutations may present with different clinical manifestations from immune dysfunction and chronic inflammation may also be implicated.
those with the classic JAK2 V617F mutation: erythrocytosis only, higher A history of any autoimmune disorder is associated with a 20 percent

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