V617F acquired somatic mutation is the most commonly described mutation associated with MPN. Current estimates suggest that the JAK2
V617F mutation is detected in >95% of patients diagnosed with PV, approximately 60% of ET patients, and 50% of PMF patients [19
]. In agreement with these reports, we detected the JAK2
V617F mutation in 95.5% of PV patients and 52.9% of PMF patients. However, ET patients in our study carried slightly higher V617F allele frequencies (68.8%) than previously reported. This might be explained by the smaller population examined in our study compared with previous study populations.
In numerous studies, the JAK2
V617F allele has been variably associated with higher indices of erythropoiesis, unchanged or decreased platelet counts, greater occurrence of thrombosis, increased BM fibrosis or cytoreductive treatments, older age, longer disease duration, or poorer survival in MPN [2
]. Similarly, it was reported that the JAK2
V617F mutation in ET or PMF patients may skew their presenting phenotype toward a more erythremic and less thrombocythemic phenotype related to high erythropoietic and granulopoietic parameters and low platelet counts [4
]. Among ET patients in our study, we observed correlations between JAK2
V617F positivity and older age, higher neutrophil fraction, higher frequency of thrombotic events, and higher myelofibrosis rates; these results are consistent with previous reports. However, we did not observe low platelet counts in JAK2
V617F-positive patients. Instead, we observed a slight tendency in groups of high JAK2
V617F allele burden to exhibit lower platelet counts among ET patients.
Similar to the JAK2
V617F mutational status, previous studies have frequently correlated JAK2
V617F allele burdens with features of stimulated erythropoiesis (e.g., elevated Hct and decreased mean cell volume, serum ferritin level, and erythropoietin level), myelopoiesis (e.g., increased WBC count, neutrophil count, and serum lactate dehydrogenase level), neutrophil activation (e.g., elevated leukocyte count and alkaline phosphatase level), and high complication rate in MPN [9
]. Compared to JAK2
V617F heterozygous patients, JAK2
V617F homozygous patients (>50% JAK2
V617F allele burden) with PV or ET exhibited significantly higher Hb levels, WBC counts, and Hct; older age; larger spleen volumes; higher incidence of pruritus; and/or more frequent progression to secondary myelofibrosis [11
]. In another study, patients with >75% JAK2
V617F allele burdens were at a higher relative risk of presenting with large spleens, pruritus, major cardiovascular events, or requiring chemotherapy compared with patients with a mutant allele burden <25%; thus, >75% JAK2
V617F allele burden at diagnosis was suggested as one of the high risk factors [10
]. A separate study also correlated the JAK2
V617F allele burden with advanced myelofibrosis and greater splenomegaly [13
V617F allele burden has been associated with disease duration in PV patients, such that the allele burden was significantly elevated in patients examined more than 5 years after their initial diagnosis [14
]. To minimize this potential bias, we limited our analyses to samples collected at each patient's initial diagnosis. However, we detected an association only between high V617F allele burden and a higher frequency of organomegaly in ET patients, but not for other clinicohematologic parameters among PV or PMF patients. PV, ET, and PMF patients with thrombotic events tended to have higher allele burdens, but this finding was not statistically significant.
Interestingly, a low JAK2
V617F allele burden at diagnosis has been proposed as a surrogate marker for shortened survival in PMF patients [17
]. In that study, the group with low V617F allele burden showed a significantly lower survival rate than the group with high V617F allele burden, but the JAK2
V617F mutational status did not affect the survival rate [17
]. In contrast, another study demonstrated that the JAK2
V617F mutation was associated with poorer survival in PMF patients [18
]. Although our short observation period precluded survival studies, previous findings support the likelihood of the JAK2
V617F allele burden as a prognostic marker in PMF patients.
Our study was limited by the small patient population, particularly for the PV and PMF patient subgroups, and by our method of JAK2
V617F allele detection. We identified JAK2
V617F from whole BM cells, whereas most previous studies have used peripheral blood granulocytes or CD34+ cells. Since JAK2
V617F is a myeloid lineage-specific mutation that is not found in lymphocytes, our analysis may have been influenced by a low detection rate [22
Although we could observe only a few associations of the JAK2 V617F allele with MPN phenotype parameters, our results support the hypothesis that the mutational status or allele burden of JAK2 V617F affects the severity of MPN-associated clinical and hematologic phenotypes with a larger allele burden, tending to produce a more severe phenotype (e.g., high myelopoiesis or high frequency of complications). Considering the limited patient number in the present study, a larger data set might improve the analysis of significance of JAK2 V617F alleles across clinical or phenotypic subgroups of MPN patients.