JAK-2 V617F mutation increases heparanase procoagulant activity

2016 ◽  
Vol 115 (01) ◽  
pp. 73-80 ◽  
Author(s):  
Inna Kogan ◽  
Dafna Chap ◽  
Ron Hoffman ◽  
Elena Axelman ◽  
Benjamin Brenner ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
Erythropoietin Receptor ◽  
Procoagulant Activity ◽  
Coagulation System ◽  
Polycythaemia Vera ◽  
Bone Marrow Biopsies ◽  
Increased Risk ◽  
V617f Mutation ◽  
Mcf 7

SummaryPatients with polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) are at increased risk of arterial and venous thrombosis. In patients with ET a positive correlation was observed between JAK-2 V617F mutation, that facilitates erythropoietin receptor signalling, and thrombotic events, although the mechanism involved is not clear. We previously demonstrated that heparanase protein forms a complex and enhances the activity of the blood coagulation initiator tissue factor (TF) which leads to increased factor Xa production and subsequent activation of the coagulation system. The present study was aimed to evaluate heparanase procoagulant activity in myeloproliferative neoplasms. Forty bone marrow biopsies of patients with ET, PV, PMF and chronic myelogenous leukaemia (CML) were immunostained to heparanase, TF and TF pathway inhibitor (TFPI). Erythropoietin receptor positive cell lines U87 human glioma and MCF-7 human breast carcinoma were studied. Heparanase and TFPI staining were more prominent in ET, PV and PMF compared to CML. The strongest staining was in JAK-2 positive ET biopsies. Heparanase level and procoagulant activity were higher in U87 cells transfected to over express JAK-2 V617F mutation compared to control and the effect was reversed using JAK-2 inhibitors (Ruxolitinib, VZ3) and hydroxyurea, although the latter drug did not inhibit JAK-2 phosphorylation. Erythropoietin increased while JAK-2 inhibitors decreased the heparanase level and procoagulant activity in U87 and MCF-7 parental cells. In conclusion, JAK-2 is involved in heparanase up-regulation via the erythropoietin receptor. The present findings may potentially point to a new mechanism of thrombosis in JAK-2 positive ET patients.

Haematopathology of classic myeloproliferative neoplasms

2020 ◽  
pp. 45-62
Author(s):  
Hans Michael Kvasnicka ◽  
Jürgen Thiele
Keyword(s):  
Continuous Improvement ◽  
Who Classification ◽  
Myeloproliferative Neoplasms ◽  
Primary Myelofibrosis ◽  
World Health ◽  
Polycythaemia Vera ◽  
The World ◽  
Health Organization ◽  
Diagnostic Importance

The classification of the World Health Organization (WHO) continues to advocate the diagnostic importance of bone marrow (BM) morphology in the diagnostic workup of myeloproliferative neoplasms (MPN). In this regard, distinctive histological BM patterns characterize specific subtypes of MPN and are the key to a meaningful clinical and molecular-defined risk stratification of patients. In this regard, the morphological denominator includes a characteristic megakaryocytic proliferation along with variable changes in the granulopoiesis and erythropoiesis. Importantly, diagnosis of MPN requires absence of relevant dysgranulopoiesis or dyserythropoiesis. In terms of clinical practice, the concept of precursor stages provides the possibility of an early intervention by appropriate therapeutic regimens that might prevent fatal complications like thrombosis and haemorrhage, especially in early stages of polycythaemia vera or in primary myelofibrosis. However, the WHO classification is not aimed to capture all biological true cases of MPN or guarantee a complete diagnostic specificity and thus might be in need of continuous improvement following clinical experience.

Evaluation of the JAK2 V617F gene mutation in myeloproliferative neoplasms cases: a one-center study from Eastern Anatolia

2019 ◽  
Vol 44 (4) ◽  
pp. 492-498
Author(s):  
Gonca Gulbay ◽  
Elif Yesilada ◽  
Mehmet Ali Erkurt ◽  
Harika Gozukara Bag ◽  
Irfan Kuku ◽  
...  
Keyword(s):  
Blood Cell ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Hematological Parameters ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Myeloproliferative Disorders ◽  
Jak2 V617f Mutation ◽  
V617f Mutation ◽  
The Difference

AbstractObjectiveDetection ofJAK2V617F in myeloproliferative neoplasms (MPNs) is very important in both diagnosis and disease progression. In our study, we investigated the frequency ofJAK2V617F mutation in patients with myeloproliferative disorders.MethodsWe retrospectively reviewed the records of 720 patients (174 females and 546 males) who were tested for JAK2 V617F mutation from January 2007 to December 2017.ResultsIn our patients were determined 22.6%JAK2V617F mutation. 33.3% in women, 19.2% in men have been positive forJAK2V617F mutation. In our studyJAK2V617F present in 48.6% of essential thrombocythemia, 80.5% of polycythemia rubra vera (PV), 47.5% of primary myelofibrosis, 10% of MPNs, unclassifiable, 0.8% of others. We also investigated the difference in hematological parameters [white blood cell, hemoglobin (Hb), hematocrit (HCT), red blood cell distribution widths (RDW) and platelets count (PLT)] betweenJAK2V617F positive andJAK2V617F negative patients.ConclusionsInvestigation of the JAK2 V617F mutation is very important in cases of MPNs. In our study JAK2 V617F mutation was higher in PV, essential thrombocythemia, and primary myelofibrosis patients. However, there were significant differences in Hb, HCT, RDW and PLT levels in mutation-positive patients.

Leukocytosis Can Predict Thrombotic Events in Myelofibrosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5191-5191
Author(s):  
Laura Coutinho Vassalli ◽  
Emilia Carolina Malafaia ◽  
Maria L. Chauffaille ◽  
Daniella Kerbauy
Keyword(s):  
Polycythemia Vera ◽  
Blood Cells ◽  
Myeloproliferative Neoplasms ◽  
Thrombotic Event ◽  
White Blood Cells ◽  
Jak2 V617f ◽  
The Other ◽  
Jak2 V617f Mutation ◽  
Increased Risk ◽  
V617f Mutation

Abstract Thrombotic events are the main complication of Philadelphia-negative chronic myeloproliferative neoplasms (MPN). In polycythemia vera (PV) and essential thrombocythemia (ET), risk factors for thrombosis are well established, such as age greater than 60 years and previous thrombosis. However, the role of JAK2 V617F mutation and leukocytosis at diagnosis as risk factor for thrombosis is still controversial. Our aim was to identify factors related to the risk for thrombotic events in the studied population.This study is a retrospective non-interventional cohort. All of the analyses were performed using the database of 142 patients with MPN regularly followed at the Hematology Division (at UNIFESP-SP) from 1992 to 2014. Diagnosis was established according to WHO criteria. We analyzed the JAK2 V617F mutation, hemoglobin (g/dL), hematocrit (%), white blood cells (x109/L) and platelets (x109/L) at the diagnosis and DIPSS-Plus risk score (International Working Group for Myelofibrosis Research and Treatment, 2009). These variables were associated with thrombotic event at any time.Of the 142 patients, 54 had diagnosis of PMF, 28 of PV, 33 of ET and 27 of post-essential thrombocythaemic myelofibrosis (post ET MF) or post-polycythaemic myelofibrosis (post-PV MF). This last group was included in myelofibrosis group for statistical purposes. Thrombotic events were more frequent in PV patients (39.2%), followed by ET (33.3%), and PMF (20.9%). From those which JAK2 mutation was obtained, it was positive in 92.4% of PV patients, 62% of PMF and 50% of ET. In none of the three groups, the presence of JAK2 V617F mutation was related to increased risk of thrombosis. In myelofibrosis, leukocytosis was higher among thrombotic patients (median of 13.7 in thrombotic group versus 9.7x 109/L; p 0.0379). None of the other parameters, hemoglobin, hematocrit, platelets and DIPSS-Plus were statistically significant. In ET, the hemoglobin level at diagnosis was significantly higher in the presence of thrombosis (mean of 14.57 in thrombotic group against 13.03 g/dL in the non-thrombotic one, p 0.0428). The other parameters, hematocrit, white blood cells and platelets were not relevant. The median WBC in the thrombotic group was 9.4 and in the non-thrombotic one 9.3 x109/L. Finally, in polycythemia vera, none of the variables were related to thrombosis. Among the studied population, leukocytosis was increased in patients with thrombotic event in MF. Thus, monitoring leukocyte count in MF is essential to predict thrombosis risk and should be further studied in order to define therapeutic goals in these patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Vladan P. Čokić ◽  
Olivera Mitrović-Ajtić ◽  
Bojana B. Beleslin-Čokić ◽  
Dragana Marković ◽  
Marijana Buač ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Myeloproliferative Neoplasms ◽  
Laboratory Data ◽  
Primary Myelofibrosis ◽  
Allele Burden ◽  
Protein Levels ◽  
Cytokine Levels ◽  
Stat Signaling ◽  
Marrow Stroma ◽  
V617f Mutation

The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs) showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34+cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV) andJAK2V617F mutation positive versus negative primary myelofibrosis (PMF) patients. Moreover, thrombocytosis was reduced byJAK2V617F allele burden in essential thrombocythemia (ET) and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34+cells of MPNs:CCND3andIL23Aregardless ofJAK2V617F allele burden;CSF3R, IL6ST, andSTAT1/2in ET and PV withJAK2V617F mutation; andAKT2, IFNGR2, PIM1, PTPN11, andSTAT3only in PV.STAT5Agene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent onJAK2V617F mutation presence in ET and PMF patients. Therefore, theJAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs.

Genomic analysis of myeloproliferative neoplasm (MPN) patients from a single institution in South Korea to reveal novel pathogenic mutations and perturbed pathways.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e19533-e19533
Author(s):  
Dilhan Weeraratne ◽  
Hu Huang ◽  
David Brotman ◽  
Shang Xue ◽  
Young Kyung Lee ◽  
...  
Keyword(s):  
Race And Ethnicity ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Genomic Analysis ◽  
Primary Myelofibrosis ◽  
Myelogenous Leukemia ◽  
Tp53 Mutations ◽  
South Korean ◽  
Pathogenic Mutations ◽  
Increased Risk

e19533 Background: Therapeutic, prognostic, and diagnostic insights gained from next generation sequencing (NGS) are a key premise of genomics-informed cancer care in hematological diseases. Particularly in BCR-ABL negative myeloproliferative neoplasms (MPN), insights gained from NGS is integral for risk stratification and prognostication. In this study, MPN patients of South Korean descent were sequenced, interpreted, and compared with a published validation cohort to identify variations in mutational profiles specific to demographics. Methods: 31 South Korean MPN patients including 12 essential thrombocythemia, 6 polycythemia vera, 6 primary myelofibrosis, and 7 chronic myelogenous leukemia were sequenced in 2018 and 2019 using the 54 gene Illumina TruSight Myeloid Panel at Hallym University College of Medicine. Orthogonal testing for CALR mutations was done by Sanger sequencing. Watson for Genomics (WfG), an artificial intelligence offering was used for variant interpretation and annotation. A cohort of 151 MPN patients previously published in the New England Journal of Medicine (NEJM) was used for comparison (PMID:24325359). Results: The table shows identified actionable mutations. Conclusions: Two novel pathogenic mutations in CALR (c.1162delG and c.1100_1145del)) were identified in Korean MPN patients. NOTCH1 pathogenic mutations were exclusive while TP53 mutations were significantly enriched in the Korean cohort suggesting that these pathways may play a role in MPN. TP53 mutations in MPN are clinically significant as they have been associated with increased risk for leukemic transformation. Of note, MPL mutations were not detected in the Korean cohort. In conclusion, race and ethnicity may contribute to some mutational signatures in cancer. [Table: see text]

Leukaemic Transformation of Philadelphia-chromosome-negative Myeloproliferative Neoplasms — A Review of the Molecular Background

2011 ◽  
Vol 07 (01) ◽  
pp. 59
Author(s):  
Nils H Thoennissen ◽  
H Phillip Koeffler ◽  
◽  
Keyword(s):  
Chromosomal Abnormalities ◽  
Myeloproliferative Neoplasms ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myeloid Cell ◽  
Primary Myelofibrosis ◽  
Haematopoietic Stem Cell ◽  
Polycythaemia Vera ◽  
Causative Role ◽  
Blast Phase

Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs), including polycythaemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythaemia (ET), are clonal haematopoietic stem cell disorders characterised by proliferation of one or more myeloid cell lineages. They are closely associated with theJAK2V617F mutation, whose detection is used as a clonal marker in the differential diagnosis of MPN. Despite recent improvements in the molecular diagnosis and therapeutic regimen of these chronic disorders, haematological evolution to blast phase remains a major cause of long-term mortality. The mechanism of MPN transformation is still a matter of some controversy because of insufficient insights into the underlying molecular pathogenesis. The purpose of this article is to summarise the increasing data concerning the mechanism of leukaemic evolution of patients diagnosed with chronic MPN. Chromosomal abnormalities and genes that have been shown to play a potential causative role in chronic-phase acceleration are discussed, as are aberrations that may serve as prognostic markers in the blast phase of MPN.

scholarly journals Portal Hypertension and Myeloproliferative Neoplasms: A Relationship Revealed

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Ahmet Burak Toros ◽  
Serkan Gokcay ◽  
Guven Cetin ◽  
Muhlis Cem Ar ◽  
Yesim Karagoz ◽  
...  
Keyword(s):  
Portal Hypertension ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Primary Myelofibrosis ◽  
Final Diagnosis ◽  
Variceal Hemorrhage ◽  
Time Treatment ◽  
Increased Risk ◽  
Long Time ◽  
Hypertension Development

Background/Objectives. Patients with myeloproliferative neoplasms have a well-established increased risk of thrombosis. Many trials report identification of an underlying myeloproliferative neoplasm by investigation of the patients developing portal hypertensive esophagus and/or fundus variceal hemorrhage in the absence of any known etiology. This trial was designed to investigate the association between myeloproliferative neoplasms and portal hypertension and to detect the frequency of portal hypertension development in this subset of patients. Methodology. Twenty-nine patients previously diagnosed with polycythemia vera, essential thrombocytopenia, and primary myelofibrosis, who were under followup at the hematology outpatient clinic of our hospital, were included in the trial. Results. In our trial, we detected portal hypertension in 13.8% of the patients (n=4), as a finding that was similar to those obtained in other studies performed to date. Conclusions. Considering the fact that diagnosis of myeloproliferative neoplasms usually takes a long time, treatment should be started (while, on the other hand, assessing the investigational and therapeutical choices for the complications) right after the bone marrow biopsy or cytogenetic studies required for establishing the final diagnosis have been performed.

scholarly journals Analysis of JAK2 V617F mutation in Tunisian patients with myeloproliferative neoplasms

2021 ◽  
Vol 19 ◽  
pp. 205873922110065
Author(s):  
Soumaya Chadi ◽  
Tarak Dhaouadi ◽  
Imen Sfar ◽  
Hela Baccouche ◽  
Rym Nabli ◽  
...  
Keyword(s):  
Mutant Allele ◽  
Myeloproliferative Neoplasms ◽  
Direct Sequencing ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Jak2 V617f Mutation ◽  
Pcr Rflp ◽  
Tunisian Patients ◽  
Healthy Control ◽  
V617f Mutation

We aimed to investigate the prevalence of the JAK2 V617F mutation in Tunisian patients with myeloproliferative neoplasms (MPN) and to look for possible associations with diseases’ presentation. In this context, JAK2 V617F polymorphism was detected by PCR-RFLP and direct sequencing in 213 MPN patients (109 with polycythemia vera (PV), 93 with essential thrombocythemia (ET) and 11 with primary myelofibrosis (PMF)), 77 unclassified patients with thrombosis (UPT) and 95 healthy control subjects. The JAK2 V617F mutant allele was present by either PCR-RFLP or direct sequencing in 158 (74.17%) MPN patients while all UPT and controls were negative. Besides, the JAK2 V617F mutation was significantly more frequent in patients with PV 98 (89.9%) than in ET 54 (58.1%) and PMF 6 (54.5%) groups, p < 0.001. Analytic results in MPN patients showed significant associations between the JAK2 SNP and both hemoglobin levels (16.29 ± 3 vs 13.01 ± 3.65) and hematocrit (52.99 ± 8.34 vs 45.37 ± 10.94), p < 0.001 and p < 0.001, respectively. In addition, in the ET subgroup thrombosis was significantly more frequent in patients carrying the V617F mutation (16, (29.6%) vs 3, (7.7%)), p = 0.01. In ET patients, the V617F mutation seems to be predictive of thrombosis occurrence.

scholarly journals Prefibrotic Primary Myelofibrosis As an Entity Distinct from Other Philadelphia-Chromosome Negative Myeloproliferative Neoplasms - Data from the Austrian Reclassification Project

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4252-4252 ◽  
Author(s):  
Georg Jeryczynski ◽  
Bettina Gisslinger ◽  
Martin Schalling ◽  
Maria Theresa Krauth ◽  
Leonhard Muellauer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloproliferative Neoplasms ◽  
Survival Rates ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Neoplasm ◽  
Primary Myelofibrosis ◽  
Distinct Entity ◽  
Bone Marrow Biopsies ◽  
Cumulative Rate ◽  
Night Sweats

Abstract Introduction: The distinction between essentialthrombocythemia(ET) and early, prefibrotic primary myelofibrosis (prePMF) by strictly applying the criteria of the WHO classification results in a newly defined subgroup of myeloproliferative neoplasm (MPN) in which the frequency and severity of clinical features are currently poorly characterized. Since prePMF was usually summarized under the subgroup of ET in previous classifications, little is known about the frequency of prePMFamong MPN. The importance of accurate diagnosis, however, is underlined by various publications that could demonstrate a significant impact on management and outcome of these patients. Aims: The aim of this study was to describe the clinical characteristics and symptoms at diagnosis of prePMF as a distinct entity and to evaluate the course of the disease in regard to survival, transformation into overt myelofibrosis and acute leukemia. Methods: All patients with representative bone marrow biopsies at presentation and complete clinical data at time of diagnosis and follow up were included in this study. All patients included were recruited from the MPN cohort of the Medical University of Vienna. Results: In total, 807 MPN patients diagnosed according to the WHO 2008 criteria were analyzed. The relative frequency of prePMF in our cohort was 17.6% (n=142) as opposed to 27.4% (221) in ET (Fig. 1). The median age for prePMF patients was 63.4 years (range 26.9-88.1) and 55.1% were female. The majority showed an elevated platelet count (median 770 G/l, range 78-2869), hemoglobin levels were on the lower end of the normal range in both genders (median 13.9, range 8.1-18.4 and 13.2, range 7.9-16.2 in men and women respectively). Leukocyte counts in the upper range of normal were common (median 9.87, range 4.0-46.0). The lactate dehydrogenase levels (LDH) were markedly elevated (median 303, range 153-729 with an institutional cut-off of 250 U/L). Therewasalso a considerate proportion of patients with splenomegaly (39.8%). Further, 22.6% of patients reported constitutional symptoms such as night sweats and weight loss. Fiber grade of 1 of a three-graded score in the bone marrow biopsy was reported in 26.2% of cases. 27.0% of patients presented withleftshiftingwith a few peripheral blasts. JAK2 positivity was found in 57.1%, CALR in 32.7 and MPL in 3.3% of cases. Only 5.9% were triple negative. 5-, 10- and 20-year survival rates were 87.6%, 67.0% and 28.8% respectively (38.2% of patients followed to death). Cumulative rate of progression into overt fibrosis was 34.2% after 10 and 58.8% after 20 years (Fig. 2). Discussion: Our data highlight important features of prePMF. Firstly, compared to ET, it has a later onset. More importantly, thrombocytosis is not a feature limited to ET, but is also frequently seen in prePMF and is therefore not suitable to accurately characterize MPN at time of diagnosis. However, leukocytosis and elevated LDH levels are features uncommon for ET as is fiber grade > 0 that is almost never seen in the WHO-defined ET, but relatively common in prePMF. Splenomegaly and presence of a few blasts are generally signs of beginningextramedullaryhematopoiesis are therefore more commonly associated with early stages primary myelofibrosis. Lastly, overall survival and fibrosis-free survival is substantially impaired in prePMF in comparison to data previously published for ET and similar to polycythemiavera. In conclusion, prePMF is a distinct entity, that while sharing some features of ET, most notably thrombocytosis, shows several striking features that should be regarded when investigating newly diagnosed MPN patients. Figure Figure. Figure Figure. Disclosures Gisslinger: Baxalta: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria.

scholarly journals Concomitant chromosome 5q-deletion and JAK2V617F mutation present with myelodysplastic and myeloproliferative overlap features

2021 ◽  
Vol 2 (2) ◽  
Author(s):  
Laura Miotke ◽  
◽  
Jay Patel ◽  
Josef T Prchal ◽  
Srinivas K Tantravahi ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Essential Thrombocytosis ◽  
Constitutive Activation ◽  
Favorable Prognosis ◽  
Chromosome 5Q ◽  
Increased Risk ◽  
5Q Deletion ◽  
Allelic Burden

Myelodysplastic Syndrome (MDS) with an isolated deletion of chromosome 5q [del(5q)] is a relatively rare MDS variant (5%) characterized by a moderate to severe anemia and normal or elevated platelet count with modest neutropenia [1-3]. These latter features, in addition to its excellent response to lenalidomide, are likely what contribute for its favorable prognosis [3-5]. The somatic gain of function mutation in JAK2 V617F is a driving mutation in Myeloproliferative Neoplasms (MPN), occurring in 97% of polycythemia vera (PV), 50-60% of essential thrombocytosis (ET) and primary myelofibrosis (PMF) [6]. This mutation results in constitutive activation of the JAK-STAT signaling pathway leading to increased proliferation and hypersensitivity to cytokines erythropoietin, IL-3, thrombopoietin, and GCSF. An allelic burden of JAK2 V617F mutation correlates with an increased risk of thrombosis and hemorrhage, as well as secondary fibrosis in MPN patients [7].

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