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JAK2 V617F

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https://www.readbyqxmd.com/read/28641646/-clinical-characteristics-and-long-term-outcome-of-125-chinese-young-patients-with-essential-thrombocythemia
#1
Rong-Feng Fu, Xiao-Fan Liu, Wei Liu, Yue-Ting Huang, Yun-Fei Chen, Hui-Yuan Li, Man-Kai Ju, Ren-Chi Yang, Lei Zhang
OBJECTIVE: To investigate the clinical characteristics and long-term outcome of Chinese young patients (≤40 years) with essential thrombocythemia(ET), and to develop a thrombosis predicting model specific for young patients with ET, so as to provide a new evidence for risk stratification and treatment. METHODS: Medical records of 125 Chinese young patients with newly diagnosed of ET were retrospectively analyzed. RESULTS: The median age at diagnosis was 32 (18-40) years old, with 37 males and 88 females...
June 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28639892/jak2-variations-and-functions-in-lung-adenocarcinoma
#2
Yanjun Xu, Juan Jin, Jiawei Xu, Yang W Shao, Yun Fan
Lung cancer ranks as the first most common cancer and the first leading cause of cancer-related death in China and worldwide. Due to the difficulty in early diagnosis and the onset of cancer metastasis, the 5-year survival rate of lung cancer remains low. JAK2 has emerged as pivotal participant in biological processes, often dysregulated in a range of cancers. Recently our study found that JAK2 might play an important role in lung cancer pathogenesis. While our understanding of JAK2 in the onset and progression of lung cancer is still in its infancy, there is no doubt that understanding the variations and functions of JAK2 will certainly secure strong biomarkers and improve treatment options for lung cancer patients...
June 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/28626521/identification-and-characterization-of-jak2-pseudokinase-domain-small-molecule-binders
#3
David E Puleo, Kaury Kucera, Henrik M Hammarén, Daniela Ungureanu, Ana S Newton, Olli Silvennoinen, William L Jorgensen, Joseph Schlessinger
Janus kinases (JAKs) regulate hematopoiesis via the cytokine-mediated JAK-STAT signaling pathway. JAKs contain tandem C-terminal pseudokinase (JH2) and tyrosine kinase (JH1) domains. The JAK2 pseudokinase domain adopts a protein kinase fold and, despite its pseudokinase designation, binds ATP with micromolar affinity. Recent evidence shows that displacing ATP from the JAK2 JH2 domain alters the hyperactivation state of the oncogenic JAK2 V617F protein while sparing the wild type JAK2 protein. In this study, small molecule binders of JAK2 JH2 were identified via an in vitro screen...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28620086/a-genetic-screen-reveals-an-unexpected-role-for-yorkie-signaling-in-jak-stat-dependent-hematopoietic-malignancies-in-drosophila-melanogaster
#4
Abigail M Anderson, Alessandro A Bailetti, Elizabeth Rodkin, Atish De, Erika A Bach
A gain-of-function mutation in the tyrosine kinase JAK2 (JAK2(V617F) ) causes human myeloproliferative neoplasms (MPNs). These patients present with high numbers of myeloid lineage cells and have numerous complications. Since current MPN therapies are not curative, there is a need to find new regulators and targets of JAK/STAT signaling that may represent additional clinical interventions. Drosophila melanogaster offers a low complexity model to study MPNs as JAK/STAT signaling is simplified with only one JAK (Hopscotch (Hop)) and one STAT (Stat92E)...
June 15, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28609766/should-we-screen-for-janus-kinase-2-v617f-mutation-in-cerebral-venous-thrombosis
#5
Matthias Lamy, Paola Palazzo, Pierre Agius, Jean Claude Chomel, Jonathan Ciron, Aline Berthomet, Paul Cantagrel, Julia Prigent, Pierre Ingrand, Mathieu Puyade, Jean-Philippe Neau
BACKGROUND: The presence of Janus Kinase 2 (JAK2) V617F mutation represents a major diagnostic criterion for detecting myeloproliferative neoplasms (MPN) and even in the absence of overt MPN, JAK2 V617F mutation is associated with splanchnic vein thrombosis. However, the actual prevalence and diagnostic value of the JAK2 V617F mutation in patients with cerebral venous thrombosis (CVT) are not known. The aims of this study were to assess the prevalence of JAK2 V617F mutation in a large group of consecutive CVT patients, to detect clinical, biological, and radiological features associated with the mutation, and to determine the long-term venous thrombosis recurrence rate in CVT patients with JAK2 mutation but without overt MPN in order to recommend the best preventive treatment...
June 14, 2017: Cerebrovascular Diseases
https://www.readbyqxmd.com/read/28602946/whole-genome-analysis-reveals-unexpected-dynamics-of-mutant-subclone-development-in-a-patient-with-jak2-v617f-positive-chronic-myeloid-leukemia
#6
I Sloma, M Mitjavila-Garcia, O Feraud, F Griscelli, N Oudrhiri, S El Marsafy, E Gobbo, D Divers, A Proust, D M Smadja, C Desterke, A Carles, Y Ma, M Hirst, M A Marra, C J Eaves, A Bennaceur-Griscelli, A G Turhan
We report here the first use of whole genome sequencing (WGS) to examine the initial clonal dynamics in an unusual patient with chronic myeloid leukemia (CML) who presented in chronic phase (CP) with doubly marked BCR-ABL1(+)/JAK2(V617F)-mutant cells and over a 9 year period progressed into an accelerated phase (AP) and then terminal blast phase (BP). WGS showed the diagnostic cells also contained mutations in ASXL1, SEC23B, MAD1L1 and RREB1, as well as 12,000 additional uncommon DNA variants. WGS of endothelial cells generated from circulating precursors revealed many of these were shared with the CML clone...
June 7, 2017: Experimental Hematology
https://www.readbyqxmd.com/read/28596259/morphologic-and-molecular-characteristics-of-de-novo-aml-with-jak2-v617f-mutation
#7
Juliana E Hidalgo-López, Rashmi Kanagal-Shamanna, L Jeffrey Medeiros, Zeev Estrov, C Cameron Yin, Srdan Verstovsek, Sergej Konoplev, Jeffrey L Jorgensen, Mohammad M Mohammad, Roberto N Miranda, Chong Zhao, John Lee, Zhuang Zuo, Carlos E Bueso-Ramos
Background:JAK2 V617F mutation (mut) in acute myeloid leukemia (AML) is rare. We describe the clinicopathologic findings of a single-institution series of 11 de novo AML cases with JAK2 V617. Methods: We identified cases of de novo AML with JAK2 V617F over a 10-year period. We reviewed diagnostic peripheral blood and bone marrow (BM) morphologic, cytogenetic, and molecular studies, including next-generation sequencing. The control group consisted of 12 patients with JAK2 wild-type (wt) AML matched for age, sex, and diagnosis...
June 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28596255/thrombotic-thrombocytopenic-purpura-associated-with-pegylated-interferon-alfa-2a-use-in-a-patient-with-polycythemia-vera
#8
Radhika Gangaraju, Soo J Kim, Jing-Fei Dong, Sabina Swierczek, Josef T Prchal
Pegylated interferon alfa-2a (pegIFNa) is being increasingly used for treatment of myeloproliferative neoplasms; however, its side effects, including autoimmune complications, are not unusual. We report on a 47-year-old woman with polycythemia vera (PV) treated with pegIFNa and in complete hematologic remission who developed thrombotic thrombocytopenic purpura (TTP). To our knowledge, thrombotic microangiopathy has been reported as a side effect of interferon (IFN) use in patients with hepatitis and chronic myeloid leukemia, but not in those with PV...
June 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28589084/calreticulin-in-essential-thrombocythemia-stressing-out-the-megakaryocyte-nucleus
#9
Francisco Jose Iborra, Petros Papadopoulos
Calreticulin (CALR) is a multifaceted protein primarily involved in intracellular protein control processes. The identification of CALR mutations in essential thrombocythemia (ET) and primary myelofibrosis that are mutually exclusive with the JAK2 V617F mutation has stirred an intensive research interest about the molecular functions of CALR and its mutants in myeloproliferative neoplasms (MPNs) and its diagnostic/prognostic value. The recently characterized protein-protein interaction of CALR mutants and MPL receptor has advanced our knowledge on the functional role of CALR mutants in thrombocythemia but it has also uncovered limitations of the current established research models...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28586872/jak2-v617f-mutation-testing-in-patients-presenting-with-hepatic-and-portal-vein-thrombosis
#10
Charles Elliott Foucar, Brady Lee Stein
No abstract text is available yet for this article.
June 6, 2017: JAMA: the Journal of the American Medical Association
https://www.readbyqxmd.com/read/28580853/-hungarian-philadelphia-negative-chronic-myeloproliferative-neoplasia-registry-evaluation-of-the-polycythemia-vera-patients
#11
Péter Dombi, Árpád Illés, Judit Demeter, Lajos Homor, Zsófia Simon, Ádám Kellner, Éva Karádi, Erika Valasinyószki, Miklós Udvardy, Miklós Egyed
Intruduction and aim: The Hungarian National Registry for Philadelphia chromosome negative myeloproliferative neoplasms has been developed. The aim of the recent study is to assess the clinical characteristics of Hungarian patients with polycythemia vera. METHOD: Data of 351 JAK2(V617F) and exon 12 mutation positive polycythemia vera patients were collected online from 15 haematology centres reporting epidemiologic, clinical characteristics, diagnostic tools, therapeutic interventions, thromboembolic complications, disease transformations...
June 2017: Orvosi Hetilap
https://www.readbyqxmd.com/read/28554272/angiogenesis-in-jak2-v617f-positive-myeloproliferative-neoplasms-and-ruxolitinib-decrease-vegf-hif-1-enesis-in-jak2-v617f-positive-cells
#12
Zhiyong Cheng, Jianzhu Fu, Guimin Liu, Lijun Zhang, Qian Xu, Su-Yun Wang
Angiogenesis and JAK2 V617F mutation are common in BCR-ABL1 negative myeloproliferative neoplasms (MPNs). Ruxolitinib, a JAK inhibitor, is an effective treatment for some MPNs. However, the relationship between angiogenesis and JAK2 V617F and the effects of ruxolitinib on angiogenesis are still unknown. Here, we observed the correlation of JAK2 V617F mutation burden with VEGF, HIF-1a and microvascular density (MVD) in MPNs. We investigate the effect of ruxolitinib on the expression of VEGF and HIF-1α in JAK2 V617F positive cells...
May 30, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28550306/a-novel-somatic-transforming-mutation-in-the-extracellular-domain-of-epidermal-growth-factor-receptor-identified-in-myeloproliferative-neoplasm
#13
D A Casolari, T Nguyen, C M Butcher, D G Iarossi, C N Hahn, S C Bray, P Neufing, W T Parker, J Feng, K Z Y Maung, A Wee, L Vidovic, C H Kok, P G Bardy, S Branford, I D Lewis, S W Lane, H S Scott, D M Ross, R J D'Andrea
We describe a novel ERBB1/EGFR somatic mutation (p. C329R; c.985 T > C) identified in a patient with JAK2(V617F) Polycythaemia Vera (PV). This substitution affects a conserved cysteine residue in EGFR domain 2 and leads to the formation of a ligand-independent covalent receptor dimer, associated with increased transforming potential. Aberrant signalling from the EGFR(C329R) receptor is cell type-dependent and in the TF1.8 erythroid cell line expression of this mutant suppresses EPO-induced differentiation...
May 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28542718/impact-of-genotype-on-leukaemic-transformation-in-polycythaemia-vera-and-essential-thrombocythaemia
#14
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
#15
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
#16
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
#17
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...
July 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
#18
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...
July 21, 2017: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/28500170/jak2-inhibitors-for-myeloproliferative-neoplasms-what-is-next
#19
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
#20
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
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