Polycythemia Vera

A number sign (#) is used with this entry because of evidence that most cases of polycythemia vera (PV) are associated with a somatic mutation in the JAK2 gene (147796) on chromosome 9p.

Somatic mutations in the TET2 gene (612839) and the NFE2 gene (601490) have also been found in cases of polycythemia vera.

Polycythemia vera, the most common form of primary polycythemia, is caused by somatic mutation in a single hematopoietic stem cell leading to clonal hematopoiesis. PV is a myeloproliferative disorder characterized predominantly by erythroid hyperplasia, but also by myeloid leukocytosis, thrombocytosis, and splenomegaly. Familial cases of PV are very rare and usually manifest in elderly patients (Cario, 2005). PV is distinct from the familial erythrocytoses (see, e.g., ECYT1, 133100), which are caused by inherited mutations resulting in hypersensitivity of erythroid progenitors to hormonal influences or increased levels of circulating hormones, namely erythropoietin (EPO; 133170) (Prchal, 2005).

Owen (1924) emphasized the familial nature of polycythemia vera and presented a possible example.

Modan (1965) suggested that in only 2 reports of familial PV was the diagnosis completely documented (Lawrence and Goetsch, 1950; Erf, 1956). Lawrence and Goetsch (1950) described 3 affected sibs. Two patients in the series of Erf (1956) were brothers and 3 others had 'a definite family history.' Modan (1965) found that polycythemia vera is more frequent in Jews than in non-Jews in the United States, but shows no simple mendelian pattern.

Levin et al. (1967) reported a curious case of 2 brothers with polycythemia vera and the Philadelphia chromosome. Subsequently, this was shown to be an instance of familial small Y chromosome (Levin, 1974).

Ratnoff and Gress (1980) described polycythemia vera in a father and son, both of whom had had intermittent exposure to organic solvents, including tetrachloroethylene and Stoddard solvent, which may have been of etiologic significance. Although the authors found 3 other well-substantiated familial occurrences of the disorder, none of them encompassed successive generations.

Budd-Chiari syndrome (600880), characterized by obstruction and occlusion of the suprahepatic veins, is a rare but typical complication in polycythemia vera patients. Cario et al. (2003) described a third pediatric case of Budd-Chiari syndrome as the initial symptom of familial polycythemia vera in an 11-year-old girl; the patient's grandmother also had polycythemia vera. The patient's mother was unaffected. The patient underwent orthotopic liver transplantation and the polycythemia vera was treated with hydroxyurea. In agreement with the clinical diagnosis, the polycythemia rubra vera-1 gene (PRV1; 162860) showed increased mRNA expression in peripheral granulocytes.

In a review of familial polycythemia vera, Miller et al. (1989) included 31 patients from 13 families.

Chen et al. (1998) presented results indicating that amplification of a gene or genes on 9p play a crucial role in the pathogenesis of PV. They observed 2 cases of PV with an extra i(9)(p10) isochromosome as the sole anomaly.

Kralovics et al. (2003) studied 6 families with PV. The familial predisposition was consistent with autosomal dominant inheritance with incomplete penetrance. However, all affected individuals showed clonal hematopoiesis, suggesting an acquired somatic nature of the disorder. Kralovics et al. (2003) concluded that multiple genetic defects are involved in PV.

Baxter et al. (2005) and Kralovics et al. (2005) found that 97% (71 of 73) and 65% (83 of 128) of patients with polycythemia vera, respectively, carried a val617-to-phe mutation (V617F; 147796.0001) in the JAK2 gene.

James et al. (2005) found that 88% (40 of 45) of patients with polycythemia vera carried the V617F mutation in JAK2. They found that the V617F mutation leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model.

In a 7-month-old girl with polycythemia vera, thrombocytosis, and increased white cell count, Kelly et al. (2008) identified the V617F mutation in blood but buccal cells, consistent with somatic mutation. Due to the risk of malignant transformation, she underwent successful allogeneic bone marrow transplantation. The findings indicated that the mutation can occur at all ages, and Kelly et al. (2008) postulated a prenatal somatic mutation in this patient.

Delhommeau et al. (2009) analyzed the TET2 gene (612839) in bone marrow cells from 320 patients with myeloid cancers and identified TET2 defects in 13 patients with polycythemia vera, all of whom also displayed the JAK2 V617F mutation.

Jutzi et al. (2013) identified 7 different somatic insertion or deletion mutations in the NFE2 gene (601490) in 8 patients with myeloproliferative disorders, including 3 with polycythemia vera and 5 with myelofibrosis (254450), either primary or secondary. In vitro studies showed that the mutant truncated NFE2 proteins were unable to bind DNA and had lost reporter gene activity. However, coexpression of mutant NFE2 constructs with wildtype NFE2 resulted in significantly enhanced transcriptional activity. Analysis of patient cells showed low levels of the mutant truncated protein, but increased levels of the wildtype NFE2 protein compared to control cells, likely due to both increased mRNA and increased stability of the wildtype protein. All 7 patients tested also carried a JAK2 V617F mutation (147796.0001). Hematopoietic cell colonies grown from 3 patients showed that the NFE2 mutation was acquired subsequent to the JAK2 mutation, and further cellular studies indicated that an NFE2 mutation conferred a proliferative advantage of cells compared to cells carrying only the JAK2 mutation. Cells carrying mutant NFE2 displayed an increase in the proportion of cells in the S phase, consistent with enhanced cell division and proliferation, and this was associated with higher levels of cell cycle regulators. These findings were replicated in mice carrying NFE2 mutations, who developed thrombocytosis, erythrocytosis, and neutrophilia.

By whole-exome sequencing and SNP array, Wang et al. (2014) analyzed 31 JAK2(V617F)-positive patients with polycythemia vera and further investigated the mutational evolution using longitudinal samples collected from 7 patients. Recurrent somatic mutations were observed in ASXL1 (612990), DNMT3A (602769), TET2, SF3B1 (605590), and PDE4C (600128). The authors identified 4 inactivating somatic mutations in ASXL1 (12.9%), 2 frameshift and 2 nonsense. All 4 loss-of-function mutations were identified in exon 12; this was a 6-fold higher mutation rate than had been reported and is similar to that of other myeloproliferative neoplasm.

Sozer et al. (2009) identified somatic homozygous JAK2 V617F mutations in liver venule endothelial cells and hematopoietic cells from 2 unrelated PV patients who developed Budd-Chiari syndrome. However, analysis of endothelial cells from a third PV patient with Budd-Chiari syndrome and in 2 patients with hepatoportal sclerosis without PV showed only wildtype JAK2. Endothelial and hematopoietic cells are believed to come from a common progenitor called the hemangioblast. Sozer et al. (2009) concluded that finding V617F-positive endothelial cells and hematopoietic cells from PV patients who developed Budd-Chiari syndrome indicates that endothelial cells are involved by the PV malignant process, and suggested that the disease might originate from a common cell of origin in some patients.

Spivak et al. (2014) used gene expression profiling to identify several molecular pathways in PV outside the canonical JAK2 pathway. CD34+ peripheral blood cells were isolated from 19 patients with PV and a somatic JAK2 V617F mutation. Men had twice as many up- or down-regulated genes compared to women, but 102 genes with differential regulation compared to controls were identified that were concordant between the sexes, suggesting a potential core set of genes involved in the pathogenesis of PV independent of gender. The pattern of expression of these genes enabled the distinction of 2 clinical subtypes: one with aggressive disease and one with indolent disease. Those with aggressive disease had lower hemoglobin levels, increased number of thromboses, splenomegaly, increased transformation to acute leukemia, and decreased survival compared to those with indolent disease. Pathways involved included histone gene deregulation, activation of the NOTCH (190198) and SHH (600725) signaling pathways, matricellular proteins, and cytokines. The findings reinforced the importance of V617F-independent expression of disease phenotype, since there was no difference in V617F allele burden between the 2 groups. Spivak et al. (2014) suggested that gene expression profiling could have prognostic relevance for patients with PV, and that identification of molecular pathways outside the JAK2 signaling pathway may have therapeutic implications.