Calr TYPE 1 and calr type 2 gene mutations determination and clinical relationship with chronic myeloproliferative disorders

Objective: Chronic myeloproliferative diseases are a group of diseases characterized by uncontrolled proliferation of one or more lines of myeloerythroid cells in bone marrow and increased number of mature or immature cells in the peripheral blood. Philadelphia (-) classic chronic myeloproliferative diseases (CMPD) mainly polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are grouped. JAK2V617F mutation identified in 2005 have been able to demonstrate clonal growth in 95-98% of PV and 50% of ET and PMF patients. Then JAK2 exon 12 mutations in PV and MPL mutations have been identified in ET and PMF. Other mutations identified in patients with CMPD is also CALR mutation. Cell proliferation is stimulated by activating STAT signaling pathway in hematopoietic cells with these mutations encoding a protein which Ca++ binding chaperone in the endoplasmic reticulum. For the first time identified in 2013 CALR mutations are shown in several hematological malignancy, lymphoid diseases and solid tumors. The frequency of CALR mutations are 50-70% in ET and 60-90% in PMF. The data is present on the effects of CALR mutations on prognosis of disease and survey and studies continues on this subject all over the world. The aim of this study is to investigate the prevalence of CALR mutations at Ph (-) CMPD patients following in outpatient clinic of haematology at Ege University Faculty of Medicine Hospital and their effects on clinical symptoms of patients with mutations in the presence of CALR. Material and Method: 35 ET, 1 PMF , 32 PV , 4 Post-PV MF and 4 Post-ET MF that a total of 76 Philadelphia (-) CMPD patients were included to the study according to 2008 WHO criteria. The demographic characteristics of the patients, clinical and laboratory data were recorded. CALR mutations were studied at 11.04.2007 date and 07-3/3 of the protocol number of the viewed with prothrombin and factor V Leiden gene mutation diagnosis of 76 CMPD patients of stored at -70°C venous blood were isolated DNA by sequence analysis method using. Pearson chi-square test, frequencies and survival analysis was used for the evaluation of istatistical analysis. Results: The mean age of the patients was 60,8 ± 13,7. Considering the age group 40-65 years of age is 64.5% of patients. There is no difference between the groups of both age and also in terms of gender. Reticulin fibers increase in the diagnosis of FMF patients was higher and was statistically significant.(p=0,001) Splenomegaly, which is correlated with stage of the disease has been detected higher in the PMF and PV cases. (p=0,001) In 19.7% of cases, thromboembolic events, including particularly myocardial infarction, cerebrovascular disease, Budd-Chiari and deep vein thrombosis was detected, but statistical differences were not found between groups. AML transformation was seen in the one of PV patients. There was no significant difference between the groups in terms of survival. JAK2V617F mutation was seen in JAK2 mutation has been evaluated in 45 patients with 20% ET, 34.4% PV and 33.3% PMF.(p>0,05) The mutation was not found in 76 cases evaluated in terms of CALR type 1 and CALR type 2 mutations. Conclusions: JAK2 and MPL mutations (-) patients with the most frequent mutations reported (approximately 80%) CALR 52-bp deletion p.L367fs*46 (Type 1 CALR mutation) and 5-bp insertion p.K385fs*47 (Type 2 CALR mutation) were not detected in our patients. CALR type 1 and type 2 mmutations show the rate of respectively 45-50% and 32-41% in the literature. However, different from the 50 mutations have been described. Studies on this subject describe of the pathogenesis as to be associated with clinical and survival will pave the way for new studies of targeted therapies. Keywords: Calreticulin, CMPD, MPN, JAK2, MPL