TET2 Mutations in essential trombocytemia and primary myelofibrosis cases

Aims: Myeloproliferative neoplasms other than CML are grouped as policytemia vera (PV), essential trombocythemia (ET) and primary myelofibrosis (PMF). PV is associated with increase in red cell mass and ET is associated with inrease in numbers of trombocytes. In addition PF is characterized by fibrosis of bone marrow. By the identification of JAK2617f mutation in 2005; the explanation of the clonal proliferation in 90-95% of PV, 50% of ET and 50% of PMF have been possible. Thereafter JAK exon-12 mutations for PV and MPL mutations for ET and PMF have been defined. However the clonal proliferation in approximately half of the PV and PMF cases have been undetermined. One of the mutations which identified in MPNs is TET2 mutation. The TET2 gene codes for a 2-oxoglutarate and Fe(II) ?dependent hydroxylase that is able to hydoxylate methylated cytosine. Its is firt defined in 2009. In addition sequencing of TET2 led to the identification of TET2 in every myeloid disorders. TET2 mutations is found positive in 15% of PV, 4-11% of ET and 19% of PMF patients. According to few cases, TET2 mutations have prognostic value. The purpose of this research is the determination of TET2 mutations and clinical relevance of TET2 in the 35 ET and 10 PMF patients who are followed up in T.C. İstanbul Bilim University Avrupa Florence Nightingale Hospital Research and Practice Center Hematology Clinic.Material and methods: 35 ET ve 10 PMF patiens are included to this research according to WHO criteria. Patients? demographic informations and clinical and laboratory findings were registered. The patients? DNAs were isolated from venous blood samplings and TET2 mutations were defined by sequence analysis. Datas were evaluated and t test, chi-squere test and Odds Ratio were performed for statistical analysis.Results: TET2 mutations were found in 47,5% (16/35) of ET patients and 70% of PMF patients. Six mutations were defined in patients who were fount TET2 positive. These mutations were I1762V, M1907T, L1721W, H1778A, C1298Y and Q1828X. L1721W and I1762V have chance to be genetic polymorphism. The frequency of ET2 mutation was not statistically different between males and females. We demonstrated a correlation between initial spleen size ant TET2 mutations for patients with ET (p=0.011). Rate of high grade fibrotic changes is found more often in bone marrow biopsy examination in TET2 mutations positive ET patients (p=0,011). Furthermore, complications including arterial thrombosis and bleeding are found more frequent in TET2 mutations positive ET and PMF patients than negative ones (for ET relatively OR:2,59, for PMF relatively OR:1,7; OR:1,6, OR:1,6). In our study we discovered that togetherness of JAK2V617F and TET2 mutations associates bigger spleen size (p=0,001). Also, risks of arterial thrombosis and bleeding are found increased in patients who have both mutations (for ET, relatively OR:3,85, OR:2,8; for PMF, relatively OR:3,67, OR:3,67). These rates are higher than only TET2 mutations positive patients.Conclusion: We demonstrated much higher TET2 mutations in patients with ET and PMF. We firstly suggest possibility of polymorphism with these high rates. Positivity of TET2 mutations are correlated with especially spleen size and rate of fibrosis for patients with ET; and these mutations increase risk of arterial thrombosis and bleeding. For patients with PMF, positivity of TET2 mutations increase spleen size and also risk of arterial thrombosis and bleeding. In both illnesses, togetherness of JAK2V617F and TET2 is associated with increased risk of complications. Double TET2 mutations positivity are correlated with severity of thrombositosis and spleenomegaly for patients with ET. This situation is found araised risk of arterial thrombosis and bleeding for patients with both ET and PMF.