Abstract
Following the identification in 2005 of the recurrent V617F mutation in exon 14 of JAK2 in Myeloproliferative Disorder (MPD) patients, many studies have confirmed the frequency of this mutation in distinct MPD subclasses. The presence of the JAK2 V617F mutation has proved even more useful to distinguish, in patients with true polycythaemia, those withPolycythaemia Vera (PV, 90% JAK2 V617F positive) from those with Idiopathic Erythrocytosis (IE, V617F-negative). The JAK2 V617F mutation is also present in about half of the patients with splanchnic vein thrombosis suggesting that occurrence of thrombosis in these patients is caused by an undiagnosed MPD.In my first study, we took advantage of our cohort of JAK2 V617F-negative patients and analyzed three distinct groups: two groups of patients with increased red cell mass, either with (PV) or without (IE) sufficient criteria for a diagnosis of PV, and one group of patients with splanchnic vein thrombosis. All patients had been previously f ...
Following the identification in 2005 of the recurrent V617F mutation in exon 14 of JAK2 in Myeloproliferative Disorder (MPD) patients, many studies have confirmed the frequency of this mutation in distinct MPD subclasses. The presence of the JAK2 V617F mutation has proved even more useful to distinguish, in patients with true polycythaemia, those withPolycythaemia Vera (PV, 90% JAK2 V617F positive) from those with Idiopathic Erythrocytosis (IE, V617F-negative). The JAK2 V617F mutation is also present in about half of the patients with splanchnic vein thrombosis suggesting that occurrence of thrombosis in these patients is caused by an undiagnosed MPD.In my first study, we took advantage of our cohort of JAK2 V617F-negative patients and analyzed three distinct groups: two groups of patients with increased red cell mass, either with (PV) or without (IE) sufficient criteria for a diagnosis of PV, and one group of patients with splanchnic vein thrombosis. All patients had been previously found negative for the JAK2 V617F mutation using allele-specific real-time polymerase chain reaction (AS-PCR).Among 47 patients with an increased red cell mass (>25% excess), 26 fulfilled the Polycythaemia Vera Study Group (PVSG) or World Health Organization (WHO) criteria for PV at diagnosis, while 21 were classified as having IE on the basis of a raised red cell mass, with no identifiable cause of secondary erythrocytosis. Eight cases were found to carry an exon 12 mutation. Thus, JAK2 exon 12 mutations were detected in 31% of our JAK2V617F negative patients, with a preponderance of the N542-E543del mutant. This quite low percentage suggests that other genetic alterations may cause PV. In conclusion, the mutations in exon 12 are very useful markers to identify MPD patients. Their frequency, unlike the JAK2 V617F mutation, is low, suggesting that the search for JAK2 exon 12 mutations should be restricted to patients who fulfil PV diagnostic criteria, have low serum Epo levels and EECs and do not carry the JAK2 V617F mutation.In the next study, I studied the 46/1 haplotype in a cohort of 170 patients with SVT (sex ratio M/F _ 1.12). As controls we studied 58 non-MPN patients with peripheral vein thrombosis (PVT) and 31 patients with JAK2VF-positive polycythemia vera (PV). We studied 2 tag single-nucleotide polymorphisms (rs10974944 and rs12343867) on peripheral blood DNA using Taqman allelic discrimination assays. In 170 patients with SVT, the frequency of the 46/1 haplotype was 0.28 which is not significantly different from the published population controls from theWellcome Trust Case Control Consortium (WTCCC) (0.24; P_.11 by the Fisher exact test). In our study, concordantly with the literature, 10 mutant allele burden was_ 50% in 89% of patients (median: 19%) whereas in the study by Smalberg et al, JAK2VF allele burden was available in 45 patients only. In summary, in a larger cohort of JAK2VF-positive patients with comprehensive mutant allele burden data, we did not confirm the higher frequency of the 46/1 haplotype in SVT patients with MPNs found by Smalberg et al.The next prospective study aimed at assessing their incidence and response to therapy. Patients with essential thrombocythemia often complain of various subjective neurological symptoms. Among thirty-seven consecutive patients with essential thrombocythemia, 11 presented with neurological symptoms. Brain magnetic resonance imagery failed to detect any substratum in patients with subjective symptoms. JAK2V617F mutation was found in 9/11 patients with neurological symptoms versus 14/26 patients without symptoms. In this prospective cohort, 30% of patients with essential thrombocythemia presented neurological symptoms. Aspirin was fully efficient in only 30% of cases. JAK2V617F mutation could be a risk factor for such symptoms.
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