Correlations of JAK2–V617F mutation with clinical and laboratory findings in patients with myeloproliferative disorders
Introduction
The identification of the JAK2–V617F mutation is an exciting new discovery in the field of chronic myeloproliferative disorders (MPDs) [1], [2], [3], [4], [5]. This acquired mutation is characterized by a G to T transversion at nucleotide 1849 in exon 12 of the JAK2 gene, leading to a substitution of valine to phenylalanine at amino acid position 617 (V617F) of the JAK2 protein [1], [2], [3], [4], [5]. The mutation is located in the JH2 pseudokinase domain of JAK2, which is involved in the auto-inhibition of its kinase activity, and results in constitutive JAK2 activation that promotes erythropoietin hypersensitivity and growth-factor independence in transfected cell lines [2], [3], [4], and induces erythrocytosis in a murine transplant model [2]. The presence of the mutation confers a proliferative and survival advantage by rendering the cells more sensitive to incoming stimulatory signals, causing clonal expansion of hematopoietic progenitors in myeloproliferative disorders [3]. Neoplastic cells can be heterozygous for the mutation or hemizygous if they are associated with loss of heterozygosity (LOH) of 9p, where JAK2 is situated [3].
The JAK2–V617F mutation has been detected in the vast majority of patients with polycythemia vera (PV) (65–97%) [1], [2], [3], [4], [5], [6] and in a lower frequency in patients with essential thrombocythemia (ET) (23–57%) [1], [2], [3], [5], [6], [7], [8], [9] and idiopathic myelofibrosis (IMF) (35–57%) [1], [2], [3], [5], [6], [10], [11]. The mutation has also been found in a small proportion of patients with systemic mastocytosis [6], [12], chronic hypereosinophilic syndrome [6], [12], chronic neutrophilic leukemia [6], [12], chronic myelomonocytic leukemia [10], [12], juvenile myelomonocytic leukemia [13], myelodysplastic syndromes [12], [14], and acute myeloid leukemia [14]. On the other hand, the mutation is absent in patients with nonhematologic cancers [14], acute and chronic lymphocytic leukemia [14], [15], [16], Hodgkin's and non-Hodgkin's lymphomas [17], and otherwise molecularly defined MPDs, such as chronic myeloid leukemia and platelet-derived growth factor receptor-rearranged eosinophilic disorders [3], [6], [14]. The explanation for JAK2–V671F yielding different chronic myeloproliferaive disease phenotypes is still unknown.
Several techniques have been applied for the detection of the mutation, as genomic DNA-PCR-sequencing [2], [3], [7], [14], RT-PCR-sequencing [4], PCR-ARMS (amplification refractory mutation system) [6], allele-specific PCR [1], [16], PCR-restriction analysis [1], [17], and real-time PCR [16]; these techniques are characterized by a different sensitivity that could justify the variety of mutation incidence in the previous studies.
To date, several groups studied the consequences of the JAK2–V617F mutation in patients with MPDs, although its role is still under investigation. In some previous series the presence of mutation has been clearly associated with a PV phenotype, with high hematocrit (Ht) and hemoglobin (Hb) levels, high white blood cell count (WBC), low erythropoietin levels and low platelet (PLT) count [2], [7], [9]. However, there are contradictory results regarding its role in thrombosis and transformation risk, as well as its long-term prognostic relevance [1], [2], [3], [7], [9]. In this study, we performed an analysis of the JAK2–V617 mutation in different groups of patients with MPDs, aiming the demonstration of its significance and its possible correlations with clinical characteristics and laboratory findings both at diagnosis and follow-up period.
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Patients
We evaluated 166 newly diagnosed and previously treated patients with MPDs (male/female: 81/85, mean age: 60.1 years, range: 25–88 years): 111 patients with ET, 43 patients with PV and 12 patients with IMF. The patients were selected from outpatient clinic between March 2005 and June 2006. In addition, we used DNA from 29 archival samples. The mean follow-up period was 39.1 months (range: 1–173 months). The Polycythemia Vera Study Group (PVSG) criteria [18] were used for the diagnosis of PV and
Prevalence of JAK2–V617F mutation in patients with MPDs
One hundred and nineteen out of 166 patients (71.6%) were positive for the presence of the JAK2–V617F mutation. More specifically, the prevalence of mutation in the different subtypes of MPDs was 81.4% in PV (35 out of 43 patients), 69.3% in ET (77 out of 111 patients) and 58.3% in IMF (7 out of 12 patients). Characteristics of the patients are shown in Table 2, which also displays the information according to JAK2–V617F mutational status. In all cases, PCR-digestion analysis confirmed the
Discussion
In support of previous reports, we observed that the JAK2–V617F mutation was present in a high proportion of our MPDs patients and it was correlated with old age and a phenotype close to PV, displaying characteristically higher Ht and Hb and lower erythropoietin levels. These patients also display a higher probability of having leucocytosis, splenomegaly and thrombotic complications at diagnosis and during the follow-up period. However, we cannot ignore the fact that the mutation occurs in
Acknowledgments
We gratefully thank Dr. Elias Zintzaras (Department of Biomathematics, University of Thessaly, School of Medicine) for statistical advice and his comments on the manuscript and Ms. Zografo Onoufriadou for her excellent technical assistance. The present study was supported in part by a grant from the General Secretariat of Research and Development of Greece (GGET, DIKTYA, No. 1215).
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2018, Seminars in HematologyCitation Excerpt :In PV, patients with a JAK2 V617F mutation do not appear to have a distinct clinical phenotype nor appear to be demographically different than those with a nonmutated JAK2 gene, although some works show that patients with the mutation have a higher white blood cell count [23,41,51]. No difference in outcomes has been described between patients with and without the JAK2 V617F mutation [23,41]. In contrast, in ET having a JAK2 V617F mutation confers a significantly different disease phenotype and prognosis.
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2016, Revista Brasileira de Hematologia e HemoterapiaIt is time to change thrombosis risk assessment for PV and ET?
2014, Best Practice and Research: Clinical HaematologyJanus kinase (JAK) 2 V617F mutation in Asian Indians with cerebral venous thrombosis and without overt myeloproliferative disorders
2012, Journal of the Neurological SciencesCitation Excerpt :Previous studies in Asian and European population have shown that JAK2 mutated patients were older than those with no mutation [10,30]. Many studies have reported higher hemoglobin/hematocrit levels in their JAK2 mutated patients [30,31]. However, these studies have been conducted in patients with overt MPD.
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2012, Clinical Lymphoma, Myeloma and LeukemiaCitation Excerpt :Patients with ET and with the JAK2 V617F mutation were found to have more pronounced activation of platelets and leukocytes.32,33 Some reports demonstrated that female sex, old age at diagnosis, higher leukocyte counts, higher risk of disease at diagnosis, hepatosplenomegaly, and high bone marrow cellularity were associated with the JAK2 gene mutation.28,34 In our data, leukocytosis, thrombocytosis, and erythrocytosis were not associated with CIR of TH events and were not associated with the JAK2 V617F mutation; only one or more cardiovascular risk factors and hepatosplenomegaly were the 2 factors associated with the JAK2 gene mutation in this study.