Discovery of JAK2V617F and the importance of JAK2 in the pathogenesis of PV

In 2005, four separate groups identified the somatic gain-of-function JAK2V617F mutation,8-11 a constitutively active allele associated with activation of downstream signaling components, including STAT3 and STAT5.8,10,34 In murine models, JAK2V617F bone marrow cells are associated with PV disease features, including erythrocytosis, leukocytosis, and enlarged spleen.10,35-38 Nearly all patients with PV have an activating mutation in JAK2, most often JAK2V617F (95% of patients) or an activating mutation in exon 12 (4% of patients).37-39 Furthermore, patients with elevated JAK2 allele burden (percentage of mutant allele relative to the total [wild type + mutant]) are at increased risk of developing post-PV MF.39

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The discovery of the JAK2V617F mutation was critical for understanding the pathobiology of PV and dovetailed with other preclinical data concerning the JAK/STAT signaling pathway. For example, GM-CSF activates JAK140 and drives granulopoiesis in a pathway that includes JAK2 in cell culture systems,41 and IL-12–driven T-cell proliferation requires JAK2 activity.42 EPO signaling through the EPO receptor activates JAK2,43 which in turn activates STAT1, STAT3, and possibly STAT5 in cell culture systems.44,45 Mice lacking JAK2 are embryonic lethal because of extreme anemia.46,47 Unlike wild-type mice, hematopoietic progenitor cells from JAK2−/− mice do not proliferate and form megakaryocytic colonies in response to thrombopoietin.47 In addition, conditional knockout of JAK2 in adult hematopoietic progenitor cells is associated with reduced viability and lowered platelet counts.48 GM-CSF antiapoptotic activity in human eosinophils requires JAK2 activation.49 Finally, JAK2 is activated in response to thrombopoietin binding to the Mpl receptor and is required for the downstream activation of STAT3.50 With the knowledge that activating mutations in JAK2 were driving the PV disease state, researchers and clinicians had the rationale for the development of new, targeted treatment options, which was the impetus for testing ruxolitinib, a potent JAK1/JAK2 inhibitor, in patients with PV.


Elevated blood counts

Elevated blood counts are one of the key diagnostic criteria associated with PV. In a large international study evaluating prognosis and survival among 1,545 patients with PV, many patients presented with elevated hemoglobin (median, 18.4 g/dL) and hematocrit values (median, 55%) at diagnosis.14 White blood cell (WBC) and platelet counts were also elevated (median, 10.4×109/L and 466×109/L, respectively).14 In addition, approximately one half of the patients presented with leukocytosis (WBC count >10.5×109/L; 49%) and thrombocytosis (platelet count ≥450×109/L; 53%).14

Patients with PV who have a high JAK2 allele burden may experience further elevated blood counts compared with those who have less allele burden. A prospective study including 173 patients with PV demonstrated that there was a correlation between the JAK2V617F allele burden and the increased risk of erythropoiesis and myelopoiesis.51 Patients with higher JAK2V617F burden at diagnosis also presented with higher hematocrit levels (regression coefficient [r] =0.67; P<0.001) and higher WBC counts (r=0.54; P<0.001).51

Thromboembolic and mortality risk

Although elevated blood counts are important diagnostic markers of PV, thromboembolic events are often responsible for the initial clinical presentation of the disease. Patients with PV are at an increased risk of cardiovascular/thromboembolic events and mortality compared with the general population.12,14,15,52 Results from a large Swedish registry database study (n=11,155 patients with PV and n=44,620 matched controls) indicated that the risk of arterial and venous thrombosis in patients with PV was five- and ninefold higher, respectively, in patients with PV compared with the general population.53

In a large, randomized, controlled trial testing cytoreductive therapy in patients with PV (CYTO-PV), elevated hematocrit levels of 45%–50% (n=183) were associated with a fourfold increase in cardiovascular complications and a significantly higher rate of cardiovascular death compared with those who had hematocrit level of <45% (n=182).20 Data from this trial also indicated that patients with a WBC count of ≥11×109/L were nearly four times more likely to experience major thrombosis when compared with those who had a WBC count of <7×109/L.54 However, available data do not suggest that thrombocytosis is a significant risk factor for cardiovascular/thromboembolic events in patients with PV. The European Collaboration on Low-Dose Aspirin in Polycythemia Vera prospective trial demonstrated that the rates of thromboembolic events and mortality were not significantly different between patients with baseline platelet counts >400×109/L vs those with lower platelet counts.55 The molecular pathway responsible for the increased incidence of thromboembolic events in patients with PV is unclear. However, data suggest that constitutive JAK2 signaling may contribute to several PV features associated with the development of thromboembolic events, including erythrocytosis,10,20 increased adhesive qualities of JAK2V617F erythrocytes,56 leukocytosis,36,54 systemic inflammation,57 and activation of blood cell types.58-65

Signs and symptoms

Patients with PV may experience a variety of disease-related symptoms, reduced QoL,52 and reduced work productivity.66 Fatigue, pruritus, difficulty in sleeping, day or night sweats, and dizziness are among the most frequently reported symptoms of PV.66 Patients with PV may also develop splenomegaly,14 which can be uncomfortable or painful in some patients.67

The specific pathways underlying PV-related symptoms are unknown, but some evidence suggests that cytokine signaling plays an important role. Notably, serum levels of inflammatory cytokines, which signal through JAK1 and/or JAK2,68 are elevated in patients with PV.69 A cytokine profiling study in patients with MF found several clinical correlations between cytokine levels, constitutional symptoms, and splenomegaly.70

Some symptoms may stem from increased blood counts caused by the constitutive activation of JAK2. The JAK2V617F mutation is associated with elevated hematocrit levels in murine models10,35,36 and in patients with PV,51 which may be associated with increased blood viscosity and symptoms that result from an impaired cerebral blood flow, including headache and dizziness.71 Patients with PV who have higher JAK2V617F allele burden may be at increased risk of developing splenomegaly and pruritus and are more frequently in need of cytoreductive therapy.39,51

The effects of PV on symptoms and QoL, as commonly measured by the MPN Symptom Assessment Form (MPN-SAF) and the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30, are similar to those of other MPNs.13 Some patients report that burdensome PV-related symptoms have negative effects on their QoL, productivity, and activities of daily living.66 In a recent US survey of 380 patients with PV, 66% experienced symptoms that reduced their QoL, 22% were sick from work for ≥1 day in the preceding 30 days, and 48% experienced PV-related interference with daily activities.66