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JAK2 V617F

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https://www.readbyqxmd.com/read/28542718/impact-of-genotype-on-leukaemic-transformation-in-polycythaemia-vera-and-essential-thrombocythaemia
#1
Alberto Alvarez-Larrán, Alicia Senín, Concepción Fernández-Rodríguez, Arturo Pereira, Eduardo Arellano-Rodrigo, Montse Gómez, Francisca Ferrer-Marin, Joaquín Martínez-López, Laura Camacho, Dolors Colomer, Anna Angona, Blanca Navarro, Francisco Cervantes, Carlos Besses, Beatriz Bellosillo, Juan Carlos Hernández-Boluda
The influence of driver mutations on leukaemic transformation was analysed in 1747 patients with polycythaemia vera or essential thrombocythaemia. With a median follow-up of 7·2 years, 349 patients died and 62 progressed to acute leukaemia or myelodysplastic syndrome. Taking death as a competing risk, CALR genotype was associated with a lower risk of transformation [subdistribution hazard ratio (SHR): 0·13, 95% confidence interval (CI): 0·2-0·9, P = 0·039], whereas JAK2 V617F showed borderline significance for higher risk (SHR: 2·05, 95% CI: 0·9-4·6, P = 0·09)...
May 23, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28538171/proliferation-drives-aging-related-functional-decline-in-a-subpopulation-of-the-hematopoietic-stem-cell-compartment
#2
Kristina Kirschner, Tamir Chandra, Vladimir Kiselev, David Flores-Santa Cruz, Iain C Macaulay, Hyun Jun Park, Juan Li, David G Kent, Rupa Kumar, Dean C Pask, Tina L Hamilton, Martin Hemberg, Wolf Reik, Anthony R Green
Aging of the hematopoietic stem cell (HSC) compartment is characterized by lineage bias and reduced stem cell function, the molecular basis of which is largely unknown. Using single-cell transcriptomics, we identified a distinct subpopulation of old HSCs carrying a p53 signature indicative of stem cell decline alongside pro-proliferative JAK/STAT signaling. To investigate the relationship between JAK/STAT and p53 signaling, we challenged HSCs with a constitutively active form of JAK2 (V617F) and observed an expansion of the p53-positive subpopulation in old mice...
May 23, 2017: Cell Reports
https://www.readbyqxmd.com/read/28509339/comparison-of-jak2-v617f-positive-essential-thrombocythaemia-and-early-primary-myelofibrosis-the-impact-of-mutation-burden-and-histology
#3
Roberto Latagliata, Nicola Polverelli, Alessia Tieghi, Giuseppe Alberto Palumbo, Massimo Breccia, Elena Sabattini, Loredana Villari, Mara Riminucci, Riccardo Valli, Lucia Catani, Giuliana Alimena, Emanuela Ottaviani, Angelo Fama, Giovanni Martinelli, Margherita Perricone, Marco Spinsanti, Michele Cavo, Nicola Vianelli, Francesca Palandri
An accurate histological diagnosis may distinguish essential thrombocythaemia (ET) from early primary myelofibrosis (early-PMF), which is associated with worse outcome. Outcome of ET is also negatively affected by the presence of the JAK2(V617F) mutation. To investigate the impact of JAK2(V617F) mutation burden and histology on outcome, we collected 475 WHO-diagnosed ET (69.2%) or early-PMF JAK2(V617F) -positive patients followed in 4 Italian haematology centers. JAK2(V617F) allele burden was ≤50% in 90% and 87% of ET and early-PMF patients, respectively (P = ...
May 16, 2017: Hematological Oncology
https://www.readbyqxmd.com/read/28502479/megakaryocytes-in-myeloproliferative-neoplasms-have-unique-somatic-mutations
#4
Belinda B Guo, Richard J Allcock, Bob Mirzai, Jacques A Malherbe, Fizzah A Choudry, Mattia Frontini, Hun Chuah, James Liang, Simon E Kavanagh, Rebecca Howman, Willem H Ouwehand, Kathryn A Fuller, Wendy N Erber
Myeloproliferative neoplasms (MPNs) are a group of related clonal hemopoietic stem cell disorders associated with hyperproliferation of myeloid cells. They are driven by mutations in the hemopoietic stem cell, most notably JAK2(V617F), CALR, and MPL. Clinically, they have the propensity to progress to myelofibrosis and transform to acute myeloid leukemia. Megakaryocytic hyperplasia with abnormal features are characteristic, and it is thought that these cells stimulate and drive fibrotic progression. The biological defects underpinning this remain to be explained...
May 11, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28501635/determining-the-role-of-inflammation-in-the-selection-of-jak2-mutant-cells-in-myeloproliferative-neoplasms
#5
Jie Zhang, Angela G Fleischman, Dominik Wodarz, Natalia L Komarova
Myeloproliferative neoplasm (MPN) is a hematologic malignancy characterized by the clonal outgrowth of hematopoietic cells with a somatically acquired mutation most commonly in JAK2 (JAK2(V617F)). This mutation endows upon myeloid progenitors cytokine independent growth and consequently leads to excessive production of myeloid lineage cells. It has been previously suggested that inflammation may play a role in the clonal evolution of JAK2(V617F) mutants. In particular, it is possible that one or more cellular kinetic parameters of hematopoietic stem cells (HSCs) are affected by inflammation, such as division or death rates of cells, and the probability of HSC differentiation...
May 10, 2017: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/28500170/jak2-inhibitors-for-myeloproliferative-neoplasms-what-is-next
#6
Prithviraj Bose, Srdan Verstovsek
Since its approval in 2011, the Janus kinase (JAK) 1/2 inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant/intolerant polycythemia vera (PV) is steadily increasing. A number of other JAK2 inhibitors have entered clinical testing, but none has been approved yet, and many discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, where survival is short...
May 12, 2017: Blood
https://www.readbyqxmd.com/read/28497580/the-evaluation-of-the-relevance-of-thrombin-generation-and-procoagulant-activity-in-thrombotic-risk-assessment-in-bcr-abl-negative-myeloproliferative-neoplasm-patients
#7
H Baccouche, M Ben Jemaa, A Chakroun, S Chadi, S Mahjoub, I Sfar, Y Gorgi, N Ben Romdhane
INTRODUCTION: It has been recently suggested that microparticles (MP) play a role in the pathogenesis of thrombotic complications. This study aimed to assess the contribution of procoagulant activity expressed by circulating MP in thrombotic events in MPN patients. METHODS: Seventy-four MPN patients were enrolled in a trans-sectional study. The MP procoagulant activity was measured using two assays: (i) the thrombin generation (TG) assay used in different conditions with the addition of both tissue factor (TF) and phospholipids (PL) and with the addition of TF or PL alone and (ii) the PROCOAG-PPL assay...
May 12, 2017: International Journal of Laboratory Hematology
https://www.readbyqxmd.com/read/28491265/experience-with-ruxolitinib-in-the-treatment-of-polycythaemia-vera
#8
REVIEW
Samah Alimam, Claire Harrison
Polycythaemia vera (PV) is a myeloproliferative neoplasm classically characterized by an erythrocytosis and is associated with a high risk of thromboembolic events, constitutional symptoms burden and risk of transformation to myelofibrosis and acute myeloid leukaemia. Therapy is directed at the haematocrit (HCT) to reduce the risk of thrombotic events and usually comprises low-dose aspirin and phlebotomy to maintain HCT at >45%. Frequently in addition, cytoreductive therapy is indicated in high-risk patients for normalizing haematological parameters to mitigate the occurrence of thromboembolic events...
April 2017: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/28484156/bcr-abl1-positive-chronic-myeloid-leukemia-emerging-in-a-patient-with-secondary-myelofibrosis-harboring-the-jak2-v617f-mutation
#9
Ayae Amemiya, Yoshikazu Ito, Yasunori Ishibashi, Yuu Saito, Seiichiro Katagiri, Tamiko Suguro, Michiyo Asano, Seiichiro Yoshizawa, Daigo Akahane, Yuko Tanaka, Hiroaki Fujimoto, Seiichi Okabe, Moritaka Gotoh, Tetsuzo Tauchi, Kazuma Ohyashiki
A 53-year-old woman with a 27-year history of myeloproliferative neoplasms came to our hospital because of a marked white blood cell count increase and progressive anemia. Clinical examination demonstrated positivity for BCR-ABL1 and JAK2-V617F mutations. She was given a diagnosis of chronic myeloid leukemia. Using the international scale, a molecular response (MR) (4.5) was achieved after treatment with dasatinib, despite the persistence of marked splenomegaly. The pathological findings of myelofibrosis were demonstrated by bone marrow biopsy...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28483676/selective-testing-for-calreticulin-gene-mutations-in-patients-with-splanchnic-vein-thrombosis-a-prospective-cohort-study
#10
Johanne Poisson, Aurélie Plessier, Jean-Jacques Kiladjian, Fanny Turon, Bruno Cassinat, Annalisa Andreoli, Emmanuelle De Raucourt, Odile Goria, Kamal Zekrini, Christophe Bureau, Florence Lorre, Francisco Cervantes, Dolors Colomer, François Durand, Juan-Carlos Garcia-Pagan, Nicole Casadevall, Dominique-Charles Valla, Pierre-Emmanuel Rautou, Christophe Marzac
BACKGROUND AND AIMS: Myeloproliferative neoplasms (MPN) are the leading cause of splanchnic vein thrombosis (SVT). JAK2(V617F) mutation is found in 80-90% of patients with SVT and MPN. Mutations of the calreticulin (CALR) gene have also been reported. However, as their prevalence ranges from 0 to 2%, the utility of routine testing can be questioned. This study aimed at identifying a group of patients with SVT at high risk of harboring CALR mutations and thus requiring this genetic testing...
May 5, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28468090/-clinical-significance-of-jak2%C3%A3-calr-and-mpl-gene-mutations-in-1-648-philadelphia-chromosome-negative-myeloproliferative-neoplasms-patients-from-a-single-center
#11
M Y Li, H Y Chao, A N Sun, H Y Qiu, Z M Jin, X W Tang, Y Han, C C Fu, S N Chen, D P Wu
Objective: To explore the prevalences of JAK2, CALR and MPL gene mutations and the mutation types in patients with Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) , and to compare their clinical characteristics of different mutation types with each other and mutation negative group. Methods: The mutations of JAK2 V617F, JAK2 gene at exon 12, CALR gene at exon 9 and MPL gene at exon 10 in 1 648 Ph negative MPNs patients were detected by direct sequencing. Results: ① The JAK2V617F mutation was found in 471 (92...
April 14, 2017: Zhonghua Xue Ye Xue za Zhi, Zhonghua Xueyexue Zazhi
https://www.readbyqxmd.com/read/28456851/ruxolitinib-reduces-jak2-p-v617f-allele-burden-in-patients-with-polycythemia-vera-enrolled-in-the-response-study
#12
Alessandro Maria Vannucchi, Srdan Verstovsek, Paola Guglielmelli, Martin Griesshammer, Timothy C Burn, Ahmad Naim, Dilan Paranagama, Mahtab Marker, Brian Gadbaw, Jean-Jacques Kiladjian
In patients with polycythemia vera (PV), an elevated JAK2 p.V617F allele burden is associated with indicators of more severe disease (e.g., leukocytosis, splenomegaly, and increased thrombosis risk); however, correlations between allele burden reductions and clinical benefit in patients with PV have not been extensively evaluated in a randomized trial. This exploratory analysis from the multicenter, open-label, phase 3 Randomized Study of Efficacy and Safety in Polycythemia Vera With JAK Inhibitor INCB018424 Versus Best Supportive Care trial evaluated the long-term effect of ruxolitinib treatment on JAK2 p...
April 30, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28446312/-clinical-characteristics-and-gene-mutations-of-gilbert-syndrome-complicated-with-myeloproliferative-neoplasm
#13
Xing-Xin Li, Jun Shi, Zhen-Dong Huang, Ying-Qi Shao, Neng Nie, Jing Zhang, Mei-Li Ge, Jin-Bo Huang, Yi-Zhou Zheng
OBJECTIVE: To investigate the clinical characteristics and gene mutations of patients with Gilbert syndrome complicated with myeloproliferative neoplasms (MPN). METHODS: Peripheral blood samples from 1 patient with Gilbert syndrome complicated with MPN and his son were collected to analyse all exon mutations of UGT1A1 gene. RESULTS: The patient with leukocytosis, thrombocythemia, mild anemia and positive JAK2/V617F mutation was initially diagnosed as MPN...
April 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28441920/investigational-janus-kinase-inhibitors-in-development-for-myelofibrosis
#14
Prithviraj Bose, Abdallah Abou Zahr, Srdan Verstovsek
Since the discovery of the activating V617F mutation in Janus kinase 2 (JAK2), a number of pharmacologic inhibitors of JAK2 have entered clinical trials for patients with myelofibrosis. However, ruxolitinib, approved in 2011, remains the only one currently available for treatment of myelofibrosis, with many others having been discontinued for toxicity, and considerable uncertainty surrounding the future of those still in development. Areas covered: The available clinical data on pacritinib and momelotinib, the two agents in the most advanced phases of clinical testing in myelofibrosis, are examined in detail...
May 8, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28439222/hemochromatosis-erythrocytosis-and-the-jak2-p-v617f-mutation
#15
EDITORIAL
Stephen E Langabeer
No abstract text is available yet for this article.
March 2017: EJIFCC
https://www.readbyqxmd.com/read/28411309/calreticulin-mutations-in-bulgarian-mpn-patients
#16
Ivan Pavlov, Evgueniy Hadjiev, Tzvetan Alaikov, Sylva Spassova, Angel Stoimenov, Elissaveta Naumova, Velizar Shivarov, Milena Ivanova
Somatic mutations in JAK2, MPL and CALR are recurrently identified in most of the cases with Philadelphia chromosome negative myeloproliferative neoplasms (MPNs). We applied four molecular genetic methods for identification of CALR exon 9 mutations, including high resolution melt (HRM) analysis, Sanger sequencing, semiconductor target genes sequencing and whole exome sequencing. A total of 78 patients with myeloid malignancies were included in the study. We identified 14 CALR exon 9 mutated cases out of 78 studied patients with myeloid malignancies...
April 14, 2017: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/28406068/clinical-and-hematological-relevance-of-jak2-v617f-and-calr-mutations-in-bcr-abl-negative-et-patients
#17
N Limsuwanachot, B Rerkamnuaychoke, S Chuncharunee, T Pauwilai, R Singdong, P Rujirachaivej, T Chareonsirisuthigul, T Siriboonpiputtana
BACKGROUND: Classical BCR-ABL1-negative myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia (ET), and primary myelofibrosis frequently harbor JAK2, MPL, and CALR somatic mutations. METHODS: AS-PCR for JAK2 V617F, pyrosequencing for MPL W515L/K, and PCR-fragment analysis for CALR exon 9 mutations were established to analyze genomic DNA isolated from peripheral blood samples of 58 newly diagnosed ET patients in Thailand. RESULTS: JAK2 V617F was detected in 41 patients (71%) and CALR exon 9 mutation was positive in eight patients (14%), whereas no mutation of MPL W515L/K was observed in this study...
April 13, 2017: Hematology (Amsterdam, Netherlands)
https://www.readbyqxmd.com/read/28405618/efficacy-of-alk5-inhibition-in-myelofibrosis
#18
Lanzhu Yue, Matthias Bartenstein, Wanke Zhao, Wanting Tina Ho, Ying Han, Cem Murdun, Adam W Mailloux, Ling Zhang, Xuefeng Wang, Anjali Budhathoki, Kith Pradhan, Franck Rapaport, Huaquan Wang, Zonghong Shao, Xiubao Ren, Ulrich Steidl, Ross L Levine, Zhizhuang Joe Zhao, Amit Verma, Pearlie K Epling-Burnette
Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples...
April 6, 2017: JCI Insight
https://www.readbyqxmd.com/read/28395787/testing-for-thrombophilia-in-mesenteric-venous-thrombosis-retrospective-original-study-and-systematic-review
#19
REVIEW
M Zarrouk, S Salim, J Elf, A Gottsäter, S Acosta
The aim was to perform a local study of risk factors and thrombophilia in mesenteric venous thrombosis (MVT), and to review the literature concerning thrombophilia testing in MVT. Patients hospitalized for surgical or medical treatment of MVT at our center 2000-2015. A systematic review of observational studies was performed. In the local study, the most frequently identified risk factor was Factor V Leiden mutation. The systematic review included 14 original studies. The highest pooled percentage of any inherited thrombophilic factor were: Factor V Leiden mutation 9% (CI 2...
February 2017: Best Practice & Research. Clinical Gastroenterology
https://www.readbyqxmd.com/read/28395559/management-of-myelofibrosis-jak-inhibition-and-beyond
#20
Maximilian Stahl, Amer M Zeidan
Myelofibrosis (MF) is characterized by bone marrow fibrosis with subsequent extramedullary hematopoiesis and abnormal cytokine expression leading to splenomegaly, constitutional symptoms and cytopenias. The discovery of the JAK2 V617F mutation in the majority of MF patients has been followed by significant progress in drug development for MF. Areas covered: In this article, we review advances in the understanding of the underlying disease biology, prognostic assessment and therapeutic modalities for MF. We provide clinical trial evidence behind using the JAK2 inhibitor ruxolitinib, erythropoiesis stimulating agents, androgens, immunomodulatory drugs, interferon, cytoreductive drugs and hypomethylating agents in MF...
April 26, 2017: Expert Review of Hematology
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