Prevalence Of JAK2V617F Mutation Research Articles

JAK2 V617F Mutation in Patients with Thrombosis

Background: Thrombosis is a major disorder with serious complications. The JAK2V617F mutation results in constitutive phosphorylation of JAK2 and activation of the cellular proliferation cascade.
 The present study aimed to clarify the prevalence of JAK2V617F mutation in patients with thrombosis.
 Subjects and Methods: This case-control study was conducted on 60 subjects subdivided into 2 groups: 30 healthy subjects as a control group (Group I) and 30 patients diagnosed with thrombosis (Group II). All subjects were subjected to full history taking, and clinical examination and investigated for Molecular detection of JAK2V617F mutation, FV (Factor V Leiden) – PTH (Prothrombin), and MTHFR (Methylene tetrahydro-folate reductase).
 Results: There was a statistically significant difference among the studied groups as regards the JAK2V617F mutation (P value < 0.05, odds ratio = 41.216, 95% C.I. 95% = 2.302 - 738.034, relative risk = 25, 95% C.I. 95% = 1.547– 404.012). This mutation was more significantly associated with venous thrombosis than arterial thrombosis (P = < 0.05).
 Conclusion: This study showed a significant association between JAK2V617F mutation and thrombosis with more significant evidence in the venous than the arterial thrombosis.

Frequency of JAK2V617F, MPL and CALR driver mutations and associated clinical characteristics in a Norwegian patient cohort with myeloproliferative neoplasms

Myeloproliferative neoplasms are hematological disorders characterized by increased production in one or more myeloid cell lines, associated with driver mutations in JAK2-, MPL- and CALR-genes. The aims of this study were to investigate the prevalence of these driver mutations in a Norwegian patient cohort with myeloproliferative neoplasms, and to assess whether the different mutations were associated with different clinical presentation and natural history. Results from 820 patients in whom analysis for JAK2V617F-, CALR- and MPL had been performed at Haukeland University Hospital in the period 2014-2019 were retrieved and analyzed together with clinical variables related to diagnosis, hematological blood parameters and complications, obtained from patient records. We identified 182 cases of myeloproliferative neoplasms: 78 with JAK2V617F, 28 with CALR-mutations, two with MPL-mutations and 23 cases without a driver mutation. There was a lower prevalence of JAK2V617F mutation than expected in the polycythemia vera group, likely related to overdiagnosis. In patients with essential thrombocytosis, we found significantly higher levels of hemoglobin and erythrocyte volume fraction for JAK2V617F-mutated disease, and significantly higher levels of platelets and lactate dehydrogenase for CALR-mutated disease. Patients with JAK2V617F-mutated primary myelofibrosis had significantly higher levels of hemoglobin, and there was an increased number of smokers or former smokers in this group compared to patients with CALR-mutations. Except for a lower prevalence of JAK2V617F-mutation in polycythemia vera, the mutational distribution in our patient cohort was similar to previous findings in other populations. The novel finding of a higher prevalence of smokers in JAK2V617F-mutated primary myelofibrosis warrants further investigation.

Characteristics of patients with cerebral sinus venous thrombosis and JAK2 V617F mutation.

Janus kinase 2 (JAK2-V617F) mutations can cause thrombocytosis, polycythemia and hyper viscosity leading to cerebral sinus venous thrombosis (CSVT). However, data regarding the characteristics and prevalence of JAK2-V617F mutation in patients with CSVT are currently lacking. We aimed to evaluate the characteristics of CSVT patients that carry the JAK2 mutation. Data of consecutive patients with CSVT, admitted to three large academic medical centers between 2010 and 2020, were retrospectively studied. Demographics, clinical presentations, radiological and clinical outcome parameters were compared between carriers of the JAK2-V617F mutation and controls. Out of 404 patients diagnosed with CSVT, 26 patients (6.5%) were carriers of the mutation. JAK2 mutation carriers more often had thrombocytosis (54% vs. 1%, p < 0.001). Furthermore, carriers of the JAK2 mutation less often had involvement of the transverse sinus (50% vs. 68%, p = 0.021). Finally, patients with the JAK2 mutation were more prone to have intracerebral hemorrhage (ICH, 31% vs. 17%, p = 0.044), but there was no significant difference between groups in terms of mortality nor functional outcome. JAK2 mutation is not uncommon in patients with CSVT and should be routinely screened for in this population. CSVT in JAK2 mutation carriers may have a tendency toward involving specific venous sinuses and is associated with a higher rate of ICH but similar overall prognosis.

Prevalence of JAK2 V617F Mutation in Iranian Patients with Myeloproliferative Neoplasms

Background and Aim: Multiple lines of evidence have been suggested that JAK2 is likely the main candidate gene responsible for the pathogenesis of myeloproliferative neoplasms. The V617F mutation in the pseudokinase domain of JAK2 protein has been detected in a majority of patients. We aimed to evaluate the frequency of this somatic missense substitution among Iranian patients with myeloproliferative neoplasms. Methods Peripheral blood samples were collected from patients with myeloproliferative neoplasms across different regions of Iran. The JAK2 V617F mutation was identified by allele-specific PCR. To confirm the PCR results, randomly selected positive and negative samples were sequenced. Results: Among 72 identified patients, 45 (62.5%) were found to harbor JAK2 V617F. The frequencies of the mutation ranged 100% for primary myelofibrosis, 75% for chronic myelogenous leukemia, 67% for polycythemia vera, 62.5% for myelodysplastic/myeloproliferative neoplasms, and 52% for essential thrombocythemia. Our findings revealed that the mutation was more common among men in comparison with women and the correlation between the mutation and gender was statistically significant (p-value<0.01). Additionally, the presence of JAK2 V617F was associated with older ages (p-value =0.009). Conclusion: The JAK2 V617F mutation was detected in 62.5% of patients with myeloproliferative neoplasms. We have shown that this single acquired point mutation was presented in at least half of the patients. Hence, it seems that the identification of JAK2 V617F mutation in myeloproliferative neoplasms can be very effective in disease diagnosing and management. *Corresponding Author: Mohammad Hamid; Email: hamidi@pasteur.ac.ir Please cite this article as: Hamid M, Shahbaz Z. Prevalence of JAK2 V617F Mutation in Iranian Patients with Myeloproliferative Neoplasms. Arch Med Lab Sci. 2020;6:1-7 (e5). https://doi.org/10.22037/amls.v6.32758

Relationship between JAK2-V617F mutation and hematologic parameters in Philadelphia-negative chronic myeloproliferative neoplasms

Abstract Objectives We aimed to investigate the prevalence of JAK2-V617F mutation and its association with hematologic parameters in polycythemia vera(PV), essential thrombocytosis(ET) and primary myelofibrosis(PMF) patients who have been tested for the mutation. Methods We retrospectively reviewed the records of 168 patients (82 males and 86 females) who were tested for JAK2-V617F mutation upon request of Hematology Clinic. JAK2-V617F mutation status, white blood cell (WBC) counts, platelet (PLT) counts, hemoglobin (Hb), hematocrit (Hct) levels and demographics of the patients were recorded. Results JAK2-V617F mutation was detected in 55.9% of the 168 patients. The mutation was observed in 58.2% of PV cases, in 54.4% of ET and in 54.5% of PMF cases. All patients were divided into two groups: mutation positive and negative. Age, WBC and PLT levels were significantly higher in mutation positive group (p&lt;0.05). Age, WBC, Hb, Hct and PLT counts in PV cases with JAK2-V617F mutation, age and WBC counts in PMF cases with JAK2-V617F mutation were found to be significantly higher compared to mutation negative patients (p&lt;0.05). Conclusion JAK2-V617F mutation is a very important parameter in diagnostic and prognostic evaluation. Thus, every patient suspected of having a myeloproliferative neoplasm should be screened for JAK2-V617F mutation.

JAK2V617F Mutation in Patient with Splanchnic Vein Thrombosis

Splanchnic vein thrombosis is an uncommon life-threatening form of venous thrombosis. It is one the common complication among MPN's. In the western studies the prevalence of JAK2V617F mutation among SVT patient is high and ranges from 7 to 59%. The frequency of this mutation among Indian SVT patients is heterogenous. This was a prospective case control study. A total 52 cases of SVT and 40 controls were screened for JAK2V617F mutation along with other routine thrombophilic risk factors. Out of total 52 cases, 10 had BCS, 2 had MVT and rest 40 were of PVT/EHPVO. The JAK2V617F mutation was seen in two cases and not in controls. Among the thrombophilic markers, heterozygous FVL mutation, PC, PS and presence of APA were seen in 2, 3, 1 and 3 cases respectively. In addition, eight cases also showed deranged risk factors (5 inherited and 3 acquired), however the repeat testing was not performed due to loss of follow up. Among controls, one person showed presence of APA and one person showed multiple thrombophilic risk factor deficiency. JAK2V617F mutation was observed in 3.8% among north Indian SVT patients. The frequency of mutation is on the lower side as compared to the available Indian data. The other thrombophilia markers (both inherited and acquired) are more frequent (18%) and patients should be routinely screened for these thrombophilia markers.

Investigation of JAK2V617F Mutation Prevalence in Patients with Beta Thalassemia Major.

Beta (β)-thalassemia major is a genetic disorder with anemia and an increased level of erythropoietin by Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway. JAK plays an important role in cell signaling, and the common mutation in the JAK2 gene in myeloid disorders is called JAK2V617F. A total of 75 patients with beta (β)-thalassemia major patients, including 34 males (45%) and 41 females (55%), were enrolled in this study. The presence of the JAK2V617F mutation was assessed using the amplification-refractory mutation-polymerase chain reaction (ARMS-PCR) technique. Among the 75 patients, 14 patients (19%) tested positive and 61 patients (81%) tested negative for JAK2V617F mutation. We observed no statistically significant difference in sex, age, genotype, and JAK2V617F mutation among patients (P> .05). However, a significant difference between blood-transfusion frequency and JAK2V617F mutation was observed (P <.05). Due to the low prevalence of JAK2V617F mutation in thalassemia, using a larger population of the patients to investigate this mutation in ineffective erythropoiesis can be useful.

PB2198 CRUCIAL AGE FOR JAK2 V617F MUTATION: GENDER DIFFERENCES

Background:The prevalence of JAK2 V617F mutation of Ph‐negative myeloproliferative neoplasias (MPN) increases with age. The dependence of the JAK2 V617F mutation prevalence and the rate of increasing its burden from the patients sex was discussion [Patterson‐Fortin J, et al., 2017; Stein BL et al., 2010]. There is monotonically increasing curve of somatic mutations and oncological morbidity as a usual presentation of growth graphs. However, the using of the population threshold model of the age dynamics of oncological diseases makes it possible to set of critical points of inflection (second order phase transition) and to quantify the intensity of the increase in the burden of disease [Landau LD, Lifshitz EM, 2013; Soukhovolsky VG et al., 2015].Aims:Assessment of the intensity of the JAK2 V617F mutation prevalence on the age and sex dependence using the model of the “second order phase transition”.MethodsThe data base of the Krasnoyarsk branch of the National Hematology Research Center from Jan 2012 to Feb 2019 examination has been used. The JAK2V617F allele burden was measured in whole blood samples by an allele‐specific quantitative polymerase chain reaction using of the “Myeloskrin JAK2 kit” (Formula of gene ltd). The relationship between the q (rate of JAK2 V617F detection) and the 1/T indicator (“reverse age”) in each age‐old five‐year cohort on 1154 men and 958 women referred with suspicion of MPN was studied. The values of q2 should be close to zero as according to the model of second order phase transitions for physical systems until reaching a certain critical patients age Tc and the relationship between the q2 and 1/T variables will be described by the equation q2 = a‐b/T with an angular coefficient b characterizing the increase in the intensity of the mutational burden with age after reaching the critical age Tc.Results:Using of our model led to transforms the monotonous growth curve of mutation prevalence with age. The value of q2 is close to zero at high values of 1/T (young patients) and for smaller values of 1/T (more older age) the relationship between q2 and 1/T becomes linear (figure). The hypothesis of the statistical significance differences of regression for male and female was tested by Fisher test for the significance level α=5%. Hypothesis of the absence of differences between the two regressions is not rejected. The critical age of patients transition to the phase with a high risk of mutation development corresponds for male Tc = 48.8 years and for female Tc = 36.0 years. Intensity of further accumulation of the mutation burden in male b = 44.35 ± 12.86, in female b = 27.52 ± 4.57.Summary/Conclusion:The “second order phase transitions model” it possible to introduce in the population analysis the indicators of the “critical age” Tc and the intensity of accumulation of the burden of mutations b. This estimate are not significantly different for male and female for our sample. The calculated critical age turned out to be significantly lower than the median of the age of diagnosis of MPN (53 and 57 years). The proposed model will be useful for analyzing the characteristics of the population of MPN in different cohorts, as well as in different social and environmental conditions of life.image

Prevalence of JAK2 V617F in Individuals That Meet World Health Organization Erythrocytosis Criteria for Polycythemia Vera

Introduction:The diagnostic criteria for polycythemia vera (PV) has recently been updated by the World Health Organization (WHO). The criterion for erythrocytosis has been modified downwards: hemoglobin (hb)> 16.5 g/dL or hematocrit (hto)> 49% in men and hb> 16 g/dL or hto> 48% in women. This reduction increases the potential number of patients that would be test for JAK2 V617F mutation if PV is suspected. The V617F mutation in the JAK2 gene is present in 95% of cases of PV. It is estimated that the prevalence of this mutation in the general population is around 0.2%. Our aims are to determine the prevalence of JAK2 V617F in individuals with erythrocytosis according to WHO2016 criteria and to find prognostic factors that could help to identify patients with PV.Methods:We prospectively studied all hemograms performed in our laboratory during 7 nonconsecutive days. Variables studied were hb, hto, leukocytes, neutrophils, platelets, MCV, MCH, MCHC and RDW. JAK2 V617F mutation was studied in all males that had hb> 16.5 g/dl or hto> 49% or females that had hb> 16 g/dl or hto> 48%. JAK2 V617F mutation was studied by PCR assay in which an amplification control fragment and the JAK2 mutant allele were simultaneously amplified. All positive samples were confirmed by quantitative real-time PCR in a reference laboratory. Positive results were considered when the JAK2 V617F allele ratio was ≥ 0.7.The variables collected were correlated with the result of the JAK2 test in a univariate way. The T-Student test was used for the quantitative variables and the Chi-square test for the categorical variables. For the cell count variables, the Mann-Whitney U test was used.Results:A total of 15366 HG were analyzed. 1271 (8.3%) met the inclusion criteria for erythrocytosis. JAK2 V617F was performed on 1001 samples (270 samples were not suitable for the PCR assay due to low quality). Twelve samples (1.2%) were positive for JAK2 V617F mutation. However, 5 samples were excluded due to a known diagnosis of myeloproliferative neoplasm. Therefore, finally prevalence of JAK2 V617 mutation in 996 patients that met WHO erythrocytosis criteria was 0.8% (8/996). Medians for all parameter studied for each group are shown in table 1. In order to find out parameters that could increase the incidence probabilities to identify patients with JAK2 V617F we performed an univariate analysis of the variables included, according to JAK2 mutational status. We found that patients with JAK2 V617F had higher levels of leukocytes, neutrophils, platelets and RDW than patients with negative JAK2 (p <0.001), while the levels of MCV (p = 0.033) and MCH (p = 0.015) were lower in patients with JAK2 V617F (table 2). For the variables that have been statistically significant, the area under the ROC curve (AUC) and the optimal cut-off point that maximizes sensitivity and specificity were calculated (Youden index). Of interest, neutrophils, platelets and RDW show high AUC (≥ 0.79), with high sensitivity and specificity (table 3). Finally, in order to find out the potential interest of these findings, we studied medical records of the 8 patients with JAK2 V617F mutations, finding that 4 patients (50%) had previously suffered a vascular event.Conclusion:The prevalence of JAK2 V617F mutation in subjects with elevated Hb or hto according to WHO2016 criteria is increased with respect to that of the general population.Among this group of subjects, those with JAK2 V617F show significantly different levels of leukocytes, neutrophils, platelets, MCV, CMH and RDW. Interestingly, neutrophils, platelets and RDW show high sensitivity and specificity. Therefore, it is necessary to explore combinations of these parameters and their optimal cut-off points to elaborate efficient strategies for an early diagnostic approach. [Display omitted] DisclosuresMartinez Lopez:Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau. García Gutiérrez:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Incyte: Honoraria, Research Funding.

Enhanced Risk for Specific Somatic Myeloproliferative Neoplastic Mutations in Patients with Stroke.

Somatic mutations of Janus kinase 2 (JAK2V617F), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) are the major clonal molecules that drive the pathogenesis of myeloproliferative neoplasms (MPN). It is well recognized that MPN patients carry an excessive risk of thrombohemorrhagic complications. However, little is known about the prevalence of these clonal markers in patients with cerebral vascular disease. To address this issue, 153 consecutive stroke patients in Taiwan were enrolled in the study. Allele-specific PCR (AS-PCR), real-time AS-PCR, and Illumina paired-end sequencing were employed to detect the presence of MPL, JAK2V617F, and CALR exon 9 mutations, respectively. JAK2V617F mutation was detectable in 13 samples (8.5%), but the allele burdens (AB) were greater than 1% in only six (3.9%) of them. Compared to JAK2-unmutated patients, those with JAK2V617F AB &gt; 1% had significantly higher white blood count (p = 0.01), although four of the six did not exhibit MPN phenotypes. Two patients had a heterozygous CALR exon9 mutation locating outside the coding region and did not alter the amino acid sequence of this protein. On the other hand, there were no patients carrying the MPL mutations. Using patient age, baseline hemogram, and stroke-relevant risk factors, we developed a predictive model that could successfully identify stroke patients at risk of carrying clonal JAK2V617F mutation. The prevalence of JAK2V617F mutation in stroke patients was higher than that seen in general population. Based on our newly developed probability stratification model, genotyping of JAK2V617F mutation in selected patients with stroke might be warranted.

JAK2V617F Promotes Atherosclerosis

Myeloproliferative disorder (MPD) patients are at high risk of atherothrombotic events including myocardial infarction and stroke. The somatic mutation (JAK2V617F) is commonly found in MPD patients and is associated with increased vascular risk. Moreover, the prevalence of JAK2V617F mutation is also significantly increased in non-MPD coronary artery disease (CAD) and peripheral artery disease (PAD) patients compared to the general population. Our goal was to investigate potential mechanisms of accelerated atherothrombosis using a JAK2V617F mouse model.Subletahlly irradiated Ldlr-/- mice were transplanted with bone marrow cells from wild type (WT) or Mx1-Cre/Jak2V617F (Jak2VF) mice and fed a high fat high cholesterol Western type diet (WTD). After 7 weeks of WTD Jak2VFmice had sustained neutrophilia, monocytosis and erythrocytosis; despite lower plasma cholesterol levels they showed ~1.6 fold larger atherosclerotic lesions in the aortic root (p=0.003) and accelerated carotid artery thrombosis (FeCl3 injury). After 12 weeks of WTD feeding, lesion area was only increased 1.3-fold compared to controls but showed features of plaque instability (increased necrotic core area). Early lesions (7 weeks) displayed significantly increased neutrophils (p=0.05, n=7) but not Mac 3+ macrophages. The increased neutrophil infiltration in Jak2VF mice correlated with atherosclerotic lesion size (p=0.001, r=0.78), suggesting a critical role of neutrophils in early atherogenesis. Advanced lesions (12 weeks) also showed significantly increased neutrophil (p=0.001) and macrophage (p=0.05) infiltration. No difference in CD3+ T cells or CD41+ platelet infiltration was observed at either time-point. In addition, five out of nine Jak2VF mice had prominent iron deposition (Prussian blue) and RBC marker Ter-119 staining in advanced atherosclerotic lesions (p<0.05). RBC marker Ter-119 co-localized with Mac-3(+) macrophages surrounding necrotic cores, indicating erythrophagocytosis and plaque instability.In summary, the Jak2V617F mutation promotes early atherosclerotic lesion development and plaque instability in advanced lesions. Neutrophil infiltration appears to be an important contributor to both early lesion development and necrotic core formation. These studies also suggest a novel role for RBC infiltration, iron deposition and erythrophagocytosis in advanced lesional necrotic core formation in JAK2V617F mice. DisclosuresLevine:Novartis: Consultancy; Qiagen: Membership on an entity's Board of Directors or advisory committees. Tall:Amgen: Consultancy; CSL Behring: Consultancy.

The Prevalence of JAK2-V617F Mutation in Sudanese Patients with Chronic Myeloproliferative Neoplasms

The Prevalence of JAK2-V617F Mutation in Sudanese Patients with Chronic Myeloproliferative Neoplasms

JAK2 V617F Analysis in Indonesian Myeloproliferative Neoplasms Patients

Background : Three subtypes of myeloproliferative neoplasms (MPNs): Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) showed overlapping phenotype. There has been no specific cytogenetic marker identified in these subtypes. JAK2 V617F mutation prevalence in Caucasian MPNs was first reported as 97% in PV, 57% in ET, and 50% in PMF.Objective: This study was done to define the prevalence of JAK2 V617F mutation and to identify cytogenetic markers in MPNs.Methods : The study design was cross-sectional. Patients who were admitted to Dr. Kariadi Hospital with clinical diagnosis of MPNs were referred for bone marrow cytogenetic analysis in Telogorejo Hospital. JAK2 V617F mutation was tested for using Amplification Refractory Mutation System Polymerase Chain Reaction (ARMS-PCR) from peripheral blood vein. Clinical data were secondary data retrieved from hospital medical records.Results : There was no cytogenetic abnormality found in all MPNs patients. The prevalence of JAK2 V617F mutation in MPNs patients was 73,68%. Mutation prevalence distribution in each subtypes were 100% in PV, 63,6% in ET and 100% in PMF. Conclusion : Chromosomal abnormality was not found using conventional cytogenetic analysis. More sensitive methods might elucidate submicroscopic chromosomal abnormalities in these patients. The prevalence of JAK2 V617F mutation was comparable with studies in Caucasian. It is recommended that JAK2 V617F testing should be incorporated in the management therapy of MPNs in Indonesia.

Neurological symptoms in essential thrombocythemia: impact of JAK2V617F mutation and response to therapy.

Patients with essential thrombocythemia (ET) often suffer from neurological symptoms (NS) not ever resulting from previous thrombotic cerebral events (TCE). We reported NS occurred in 282 patients, in order to identify the factors influencing ET-related NS in the absence of TCE, and the response to therapy. Overall, 116 of 282 patients (41%) presented NS; 101 of them (87%) reported subjective transient and fluctuating NS, without concurrent TCE, which we defined as ET-related NS, by frequency: cephalalgia, chronic paresthesias, dizziness or hypotension, visual disturbances, and tinnitus. In univariate analysis, ET-related NS resulted more frequently in young people (P=0.017) and in females (P=0.025). We found a higher prevalence of JAK2V617F mutation in ET-related NS patients (P=0.021). In multivariate analysis, gender (P=0.024) and JAK2V617F mutation (P=0.041) remained significantly associated with the development of ET-related NS, with a risk of about four times higher for JAK2V617F-mutated patients (OR=3.75). Ninety-seven of 101 patients with ET-related NS received an antiplatelet (AP) agent at the time of NS, whereas only selected high-risk ET-related NS patients were treated with a cytoreductive drug, according to the published guidelines and similarly to patients without NS. We observed that only 32 of 97 (33%) patients with ET-related NS achieved a complete response after AP treatment. Among the 65 non-responder patients, 36 (55.4%) improved NS after the introduction of cytoreductive therapy; therefore, the addition of cytoreductive treatment should be considered in this setting.

Prevalence of JAK2V617F mutation in deep venous thrombosis patients and its clinical significance as a thrombophilic risk factor: Indian perspective.

Venous thromboembolism is known to be a complex interaction of genetic and acquired factors leading to thrombosis. JAK2V617F mutation is believed to contribute to a thrombophilic phenotype, possibly through enhanced leukocyte-platelet interactions in myeloproliferative neoplasms (MPNs). Several studies have focused on the importance of screening for JAK2V617F mutation in patients with splanchnic venous thrombosis (VT) for the detection of nonovert MPNs. The role of JAK2V617F mutation in VT outside the splanchnic region is still widely unsettled. The primary aim of this study was to find out the prevalence of JAK2V617F mutation in patients with deep venous thrombosis (DVT), its clinical significance as a prothrombotic risk factor, and its possible interactions with other genetic thrombophilic risk factors. A total of 148 patients with idiopathic, symptomatic DVT were evaluated. Median age of presentation was 32 years (range 15-71 years) with a sex ratio of 1.3:1. Overall, the most common genetic prothrombotic factor was factor V Leiden mutation, found in 10.8% (16 of 148) of patients who also showed strong association with increased risk of thrombosis (odds ratio 5.94, confidence interval 1.33-26.4, P = .019). Deficiencies in protein C, protein S, and antithrombin were seen in 8 (5.4%), 10 (6.7%), and 8 (5.4%) patients, respectively. It was observed that the frequency of JAK2V617F mutation was lower in Indian patients, and it also showed weaker association with risk of thrombosis, at least in cases of venous thrombosis outside the splanchnic region.

Prevalence of the JAK2 V617F Mutation in Patients with Peripheral Arterial Disease

Introduction:The acquired JAK2 V617F mutation is common in patients with myeloproliferative neoplasms and increases thrombotic risk. We previously showed that JAK2 V617F is also found in healthy subjects as well as in patients with coronary artery disease (0.6% and 1.3%, respectively). Peripheral arterial disease (PAD) is an important manifestation of diffuse atherosclerosis and PAD patients are at exceptionally high risk for cardiovascular events, showing a worse prognosis than that of patients with coronary artery disease Due to the close relation of the JAK2 V617F mutation to thrombotic events we hypothesized that this mutation may play an important role in the risk management of PAD patients. However, prevalence of JAK2 V617F or of occult myeloproliferative neoplasms is unknown in PAD patients.Methods:In the present study we determined the prevalence of JAK2 V617F in a cohort of 287 patients with sonographically proven PAD. JAK2 mutational status from 997 age-matched healthy people was available from a previous study. JAK2 V617F screening and quantification of allele burden in both cohorts was performed with allele-specific quantitative real-time PCR.Results:From a total of 287 PAD patients samples, 9 (3.1%) were tested positive for JAK2 V617F mutation corresponding to a 5-fold, highly significant increase compared with healthy people (p<0.001). Mutant allele burden of JAK2 V617F positive samples was ranging between 0.2% and 96.2% (median=0.75%). Generally, our study showed no significant association of the JAK2 V617F mutation with abnormal blood cell counts. However, the patient with the highest mutant allele burden showed elevated hemoglobin values (> 18.5 g/dL) indicating polycythemia vera (PV).Conclusion:We conclude that the prevalence of JAK2 V617F mutation is significantly increased in PAD patients compared to the general population. For this reason mutation analysis should be considered in PAD patients with abnormal blood cell counts to identify occult myeloproliferative neoplasms and to adjust therapeutic treatment, possibly reducing the risk of future vascular complications. DisclosuresNo relevant conflicts of interest to declare.

Occurrence of the JAK2 V617F mutation in patients with peripheral arterial disease.

The acquired JAK2 V617F mutation is common in patients with myeloproliferative neoplasms. We previously showed that JAK2 V617F is also found in coronary patients, most of them affected by coronary atherosclerosis. Peripheral arterial disease (PAD) is another important manifestation of atherosclerosis. However, prevalence of the JAK2 V617F mutation and its effect on clinical or hematologic characteristics is unknown in PAD patients. In the present study we determined the prevalence of JAK2 V617F in a cohort of 287 patients with sonographically proven PAD and compared mutation frequency with mutational status of 997 healthy people from the KORA F4 study. JAK2 V617F screening and quantification of allele burden in both cohorts was performed with same allele-specific quantitative real-time PCR method. From a total of 287 PAD patients, 9 individuals were tested positive for the JAK2 V617F mutation. One patient showed elevated hemoglobin values, indicating polycythemia vera. Observed JAK2 V617F frequency (3.1%) in PAD patients showed a 5-fold, highly significant increase compared with healthy people (P < 0.001). Furthermore, occurrence of the mutation in PAD patients was significantly decreased in patients using aspirin (P = 0.003). We conclude that the prevalence of JAK2 V617F mutation is significantly increased in PAD patients compared to the general population. Future studies are warranted to confirm our observations and to define the underlying mechanisms behind our findings.

JAK2V617F+ myeloproliferative neoplasm clones evoke paracrine DNA damage to adjacent normal cells through secretion of lipocalin-2

AbstractGenetic instability is strongly involved in cancer development and progression, and elucidating the mechanism could lead to novel therapeutics for preventing carcinogenesis. Philadelphia-negative myeloproliferative neoplasms (MPNs) are clonal myeloid disorders with a high prevalence of JAK2V617F mutation, and transformation to acute myeloid leukemia through accumulation of additional mutations is a major complication in MPNs. Here, we showed that JAK2V617F+ cells conferred paracrine DNA damage to neighboring normal cells as well as to themselves through increased reactive oxygen species (ROS). We screened candidate factors responsible for the effect and found that lipocalin-2 (Lcn2) is overexpressed in JAK2V617F+ cells and that short hairpin RNA–mediated knockdown of Lcn2 significantly alleviated the paracrine DNA damage. Normal hematopoietic cells showed elevated ROS levels through increased intracellular iron levels when treated with lipocalin-2, which led to p53 pathway activation, increased apoptosis, and decreased cellular proliferation. In contrast, JAK2V617F+ cells did not suffer from lipocalin-2–induced growth suppression resulting from attenuated p53 pathway activation, which conferred a relative growth advantage to JAK2V617F+ clones. In summary, we demonstrated that JAK2V617F-harboring cells cause paracrine DNA damage accumulation through secretion of lipocalin-2, which gives proliferative advantage to themselves and an increased risk for leukemic transformation to both JAK2V617F+ and JAK2V617F– clones.

DETECTION OF JAK-2 MUTATION BY PCR TECHNIQUE IN CHRONIC MYELOPROLIFERATIVE DISORDERS

At this study we aimed to detect the prevalence of JAK2 V617F mutation in various myeloproliferative neoplasms (MPNs) that represent a major advance in molecular understanding of CMPN disorders in order to identify its diagnostic value. In this study we evaluated it's clinical and laboratory correlates in 40 patients with MPNs. The mutation was detected by allele-specific PCR. The mutation was detected in 8 patients: 80% (8/10) of those with polycythemia vera, 63.6% (7/11) of those with essential thrombocythemia, 62.5% (5/8) of those with chronic idiopathic myelofibrosis and 0% (0/11) of those with chronic myeloid leukemia. The patients carrying the mutation were older (p = 0.003) and have splenomegaly in polycythemia vera group (p = 0.05) but no statistical difference was found between positive and negative JAK2 carriers as regarding HB, TLC ,PLTs count or gender type (P > 0.05). This study implies that the JAK2–V617F mutation may be useful for the diagnosis, classification and the management of patients with MPDs. Keywords: JAK2 V617F; Polycythemia vera; Essential thrombocythemia; chronic Idiopathic myelofibrosis; Myeloproliferative neoplasms.

Prevalence of JAK2 V617F mutation in west algerian population with chronic myeloproliferative neoplasms: A multicenter study

JAK2 V617F point mutation is now well recognized in patients with chronic myeloproliferative neoplasms (MPNs). However, its frequency in Algerian patients is still unknown. We determined the JAK2 V617F mutation in blood samples from 344 patients from five hematology departments across West Algeria, using amplification refractory mutation system-polymerase chain reaction (ARMSPCR). The JAK2 V617F mutation was identified in 157/344 patients (45.63%), 80/98 polycythemia vera patients (81.6%), 44/75 essential thrombocythemia patients (58.6%), 6/13 primary myelofibrosis patients (46.2%), 21/87 with suspected MPN (12.9%), and 2/32 secondary thrombocytosis patients (6.2%), but was not detected in 28 patients with secondary erythrocytosis. Detection of JAK2 V617F mutation is an essential molecular tool to establish myeloproliferative neoplasm diagnosis, which allowed us to adjust the diagnosis for 6 patients and should be systematically included into the initial evaluation of patients suspected of MPNs in Algeria.