Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032463 (polycythemia vera)
 3,374 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular manifestations are the main clinical complication of essential thrombocythemia (ET). They include arterial thrombosis (30-40% of patients), venous thrombosis (5%), and ischemia due to microcirculatory disorders. Their incidence is highest at disease onset and diminishes gradually thereafter. The pathophysiology of ET involves dysmegakaryocytopoiesis, leading to platelet, leukocyte and vascular endothelial cell activation. The recent discovery of the V617F mutation of the JAK2 tyrosine kinase in 50-60% of patients with ET defined a new subgroup resembling polycythemia vera. This review examines biological findings and their correlation with the risk of thrombosis. Until now, stratification of the vascular risk has relied on a clinical case-control study showing that thrombotic and vascular complications are more frequent in patients over 60 and those with a history of thrombosis. These criteria, along with a rapid increase in thrombocytosis (>1500 G/L) leading to an increase in the bleeding risk, define a high-vascular-risk subgroup of patients warranting cytoreductive therapy. Although many biological markers of dysmegakaryocytopoiesis and cellular hyperactivation have been linked to an increase in the thrombotic risk, none is available for large-scale prediction of an intermediate vascular risk. The role of the JAK2 V617F mutation itself is controversial. Whatever the ET subgroup, antiplatelet therapy is largely used, based on the results of the ECLAP prospective controlled trial that showed a statistically significant reduction in thrombotic complications in patients receiving aspirin for polycythemia vera, a very similar myeloproliferative disorder.
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PMID:[Vascular complications of essential thrombocythemia]. 1807 51

The Janus family of non-receptor tyrosine kinases (JAK1, JAK2, JAK3 and tyrosine kinase 2) transduces signals downstream of type I and II cytokine receptors via signal transducers and activators of transcription (STATs). JAK3 is important in lymphoid and JAK2 in myeloid cell proliferation and differentiation. The thrombopoietin receptor MPL is one of several JAK2 cognate receptors and is essential for myelopoiesis in general and megakaryopoiesis in particular. Germline loss-of-function (LOF) JAK3 and MPL mutations cause severe combined immunodeficiency and congenital amegakaryocytic thrombocytopenia, respectively. Germline gain-of-function (GOF) MPL mutation (MPLS505N) causes familial thrombocytosis. Somatic JAK3 (e.g. JAK3A572V, JAK3V722I, JAK3P132T) and fusion JAK2 (e.g. ETV6-JAK2, PCM1-JAK2, BCR-JAK2) mutations have respectively been described in acute megakaryocytic leukemia and acute leukemia/chronic myeloid malignancies. However, current attention is focused on JAK2 (e.g. JAK2V617F, JAK2 exon 12 mutations) and MPL (e.g. MPLW515L/K/S, MPLS505N) mutations associated with myeloproliferative neoplasms (MPNs). A JAK2 mutation, primarily JAK2V617F, is invariably associated with polycythemia vera (PV). The latter mutation also occurs in the majority of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). MPL mutational frequency in MPNs is substantially less (<10%). In general, despite a certain degree of genotype - phenotype correlations, the prognostic relevance of harbouring one of these mutations, or their allele burden when present, remains dubious. Regardless, based on the logical assumption that amplified JAK-STAT signalling is central to the pathogenesis of PV, ET and PMF, several anti-JAK2 tyrosine kinase inhibitors have been developed and are currently being tested in humans with these disorders.
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PMID:JAK and MPL mutations in myeloid malignancies. 1829 15

JAK2 is a tyrosine kinase involved in cytokine signaling. The JAK2V617F point mutation, first described in 2005, results in constitutive activation of JAK2 and is now widely used as a diagnostic marker for Philadelphia chromosome negative myeloproliferative neoplasms. In recent years, more novel JAK2 mutations and fusion genes have been discovered in myeloproliferative neoplasms and other hematologic malignancies. This review aims to summarize the discovery and use of the JAK2V617F point mutation, other novel JAK2 mutations, and JAK2 translocations in diagnosing myeloproliferative neoplasms, acute myeloid leukemia, and acute lymphoid leukemia. JAK2 mutation testing is addressed, including the sensitivity and specificity of the different JAK2 mutation testing methods, clinical indications for use, and the use of quantitative JAK2 mutation testing for routine pathologic diagnosis, prognosis, and monitoring response to therapy. The relationship of JAK2 mutation to endogenous erythroid colony formation, thrombopoietin receptor mutation, polycythemia rubra vera-1 overexpression, and thrombopoietin receptor underexpression in myeloproliferative neoplasms are explored. Also discussed are the JAK2 inhibitors for clinical trials. Finally, the advantages of the newly proposed World Health Organization classification for myeloproliferative neoplasms are reviewed.
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PMID:The saga of JAK2 mutations and translocations in hematologic disorders: pathogenesis, diagnostic and therapeutic prospects, and revised World Health Organization diagnostic criteria for myeloproliferative neoplasms. 1853 68

The JAK2V617F mutation is an essential oncogenic event in Philadelphia negative chronic myeloproliferative disorders (Ph-cMPD). It is still unclear how a unique tyrosine kinase mutation can give rise to the broad clinical and morphologic spectrum of Ph-cMPD. One possible explanation could be differences in the JAK2V617F gene dosage, or different maturation stages on which myeloid lineages are affected by the mutation. The extent of lymphoid lineage involvement in JAK2V617F-positive cMPD is still controversial. We comparatively studied the zygosity status of microdissected megakaryocytes, nonmegakaryocytic hematopoietic cells, and reactive as well as neoplastic lymphoid nodules from bone marrow trephines of 61 patients with Ph-cMPD. The presence of the mutation and mutant gene dosage were determined by allele-specific polymerase chain reaction and TaqMan analysis, respectively. The mutation was detected in 22/32 (68%) cases of essential thrombocythemia, all cases of polycythemia vera, and 4/8 (50%) idiopathic myelofibrosis. Comparison of whole bone marrow sections and the different myeloid lineages showed similar percentages of the mutated allele. Restriction to a particular lineage or major differences in allele dosage were not observed, except for 2 cases in which megakaryocytes revealed a higher frequency of the mutated allele. A heterozygous JAK2V617F mutation was detected in 3/8 "reactive" lymphoid nodule in patients with Ph-cMPD, whereas all concomitant non-Hodgkin lymphoma of B-cell type were negative. These results demonstrate that different myeloid lineages usually show similar frequencies of the JAK2V617F allele. The occasional detection of JAK2V617F in benign lymphocytes points to involvement of the lympho-myeloid stem cell.
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PMID:Quantitation of the JAK2V617F mutation in microdissected bone marrow trephines: equal mutational load in myeloid lineages and rare involvement of lymphoid cells. 1855 50

The Philadelphia chromosome-negative myeloproliferative disorders (MPDs) polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (PMF) are characterized by increased proliferation of terminally differentiated myeloid cells. Although these disorders were recognized as clonal hematopoietic stem cell disorders more than 3 decades ago, little was known about the genetic basis for these disorders until 2005 when a single recurrent mutation in the JAK2 tyrosine kinase (JAK2V617F) was identified in >90% of patients with PV and in a significant proportion of patients with ET and PMF. JAK2V617F is a constitutively active tyrosine kinase and has transforming properties in vitro and in vivo, providing validation JAK2V617F is a bona fide oncogene which contributes to MPD pathogenesis. Subsequent studies of JAK2V617F-negative MPDs have identified mutations in JAK2 exon 12 and MPL, and these mutations also result in constitutive activation of JAK2 signaling. In this review, we will discuss the genetics of PV, ET and PMF with regard to known somatic mutations, the role of these mutations in hematopoietic transformation and the therapeutic implications of these findings.
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PMID:JAK2 and MPL mutations in myeloproliferative neoplasms. 1856 40

Jak2 tyrosine kinase is essential for animal development and hyperkinetic Jak2 function has been linked to a host of human diseases. Control of this pathway using Jak2-specific inhibitors would therefore potentially serve as a useful research tool and/or therapeutic agent. Here, we used a high-throughput program called DOCK to predict the ability of 20,000 small molecules to interact with a structural pocket adjacent to the ATP-binding site of murine Jak2. One small molecule, 2-methyl-1-phenyl-4-pyridin-2-yl-2-(2-pyridin-2-ylethyl)butan-1-one (herein designated as Z3), bound to Jak2 with a favorable energy score. Z3 inhibited Jak2-V617F and Jak2-WT autophosphorylation in a dose-dependent manner but was not cytotoxic to cells at concentrations that inhibited kinase activity. Z3 selectively inhibited Jak2 kinase function with no effect on Tyk2 or c-Src kinase function. Z3 significantly inhibited proliferation of the Jak2-V617F-expressing, human erythroleukemia cell line, HEL 92.1.7. The Z3-mediated reduction in cell proliferation correlated with reduced Jak2 and STAT3 tyrosine phosphorylation levels as well as marked cell cycle arrest. Finally, Z3 inhibited the growth of hematopoietic progenitor cells isolated from the bone marrow of an essential thrombocythemia patient harboring the Jak2-V617F mutation and a polycythemia vera patient carrying a Jak2-F537I mutation. Collectively, the data suggest that Z3 is a novel specific inhibitor of Jak2 tyrosine kinase.
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PMID:Z3, a novel Jak2 tyrosine kinase small-molecule inhibitor that suppresses Jak2-mediated pathologic cell growth. 1872 78

Although it has long been known that the myeloproliferative neoplasms (MPN) polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are clonal hematopoietic stem-cell disorders, for many years the genetic basis for these disorders was elusive. A new era in MPN biology began in 2005 with the discovery of a somatic point mutation in JAK2 tyrosine kinase (JAK2V617F), which was identified in a significant proportion of patients with PV, ET and PMF. Based on the hypothesis that JAK-STAT signaling is central to the pathogenesis of JAK2V617F-negative MPN, genomic studies have identified JAK2 exon 12 mutations in JAK2V617F-negative PV and activating mutations in MPL in patients with JAK2V617F-negative ET and PMF. In this review, we will discuss the role of these mutant alleles in the pathogenesis of PV, ET and PMF, the potential therapeutic implications of these discoveries, and the implications of these discoveries for genomic studies of hematopoietic malignancies.
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PMID:JAK2 and MPL mutations in myeloproliferative neoplasms: discovery and science. 1875 26

In 1951 William Dameshek classified polycythemia vera (PV), essential thombocytosis (ET), and primary myelofibrosis (PMF) as pathogenetically related myeloproliferative disorders (MPD). Subsequent studies demonstrated that PV, ET, and PMF are clonal disorders of multipotent hematopoietic progenitors. In 2005, a somatic activating mutation in the JAK2 nonreceptor tyrosine kinase (JAK2V617F) was identified in most patients with PV and in a significant proportion of patients with ET and PMF. Subsequent studies identified additional mutations in the JAK-STAT pathway in some patients with JAK2V617F(-) MPD, suggesting that constitutive activation of this signaling pathway is a unifying feature of these disorders. Although the discovery of mutations in the JAK-STAT pathway is important from a pathogenetic and diagnostic perspective, important questions remain regarding the role of this single disease allele in 3 related but clinically distinct disorders, and the role of additional genetic events in MPD disease pathogenesis. In addition, these observations provide a foundation for development of small molecule inhibitors of JAK2 that are currently being tested in clinical trials. This review will discuss our understanding of the pathogenesis of PV, ET, and PMF, the potential role of JAK2-targeted therapy, and the important unanswered questions that need to be addressed to improve clinical outcome.
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PMID:Myeloproliferative disorders. 1877 4

Recent studies shed new lights on the biological function of blood group antigens, such as the adhesion properties of the Lutheran (Lu) blood group antigens carried by the Lu/BCAM glycoproteins. The Lu/BCAM adhesion glycoproteins were first identified as laminin-10/11 erythroid receptors involved in RBC adhesion to endothelium in sickle cell anemia. Lu/BCAM mediated cell adhesion to laminin is stimulated by epinephrine, a physiological stress mediator, and is dependent of phosphorylation by protein kinase A. More recently, we demonstrated that constitutive phosphorylation of Lu/BCAM is also involved in abnormal RBC adhesion to endothelium in patients with polycythemia vera (PV), a frequent myeloproliferative disorders associated with the V617F mutation of the tyrosine kinase JAK2 leading to continuous stimulation of erythropoiesis. This observation suggests that Lu/BCAM could participate to the high incidence of vascular thrombosis that also characterizes PV disease. In mice, which do not express Lu/BCAM in erytroid tissues, invalidation of the Lu/BCAM gene provided evidence that Lu/BCAM gps, as laminin-alpha5 receptors, are involved in vivo in the maintenance of normal basement membrane organization in different non erythroid tissues since up to 90% of the mutant kidney glomeruli exhibited a reduced number of visible capillary lumens and irregular thickening of the glomerular basement membrane, while intestine exhibited smooth muscle coat thickening and disorganization. All these results further illustrate that minor blood group antigens might have important role under physiological and physiopathological conditions in erythroid and non erythroid tissues as well.
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PMID:Red cell and endothelial Lu/BCAM beyond sickle cell disease. 1894 49

Essential thrombocythemia (ET) is a hematopoietic disorder that manifests clinically as thrombocytosis, and patients with ET are at increased risk for developing thrombosis, myelofibrosis, and transformation to acute myeloid leukemia. Although ET was recognized as a distinct clinical syndrome more than 6 decades ago and was classified as a myeloproliferative neoplasm (MPN) by William Dameshek in 1951, the molecular pathogenesis of ET remained unknown until 2005, when activating mutations in the JAK2 tyrosine kinase (JAK2V617F) were identified in a significant proportion of patients with ET, polycythemia vera (PV) and primary myelofibrosis (PMF). In addition, subsequent studies have identified gain-of-function mutations in the thrombopoietin receptor (MPL) in a subset of patients with JAK2V617F-negative ET, suggesting that JAK2 activation by distinct mechanisms contributes to the pathogenesis of ET. Despite these important observations, important questions remain regarding the role of JAK2/MPL mutations in ET pathogenesis, the etiology of JAK2/MPL negative ET, the factors that distinguish ET from other MPNs with the JAK2V617F mutation, and the role of JAK2-targeted therapies for the treatment of these MPNs.
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PMID:New advances in the pathogenesis and therapy of essential thrombocythemia. 1907 62


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