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)

Polycythemia vera (PV) is a clonal stem cell disorder characterized by hyperproliferation of the erythroid, myeloid, and megakaryocytic lineages. Although it has been shown that progenitor cells of patients with PV are hypersensitive to several growth factors, the molecular pathogenesis of this disease remains unknown. To investigate the molecular defects underlying PV, we used subtractive hybridization to isolate complementary DNAs (cDNAs) differentially expressed in patients with PV versus normal controls. We isolated a novel gene, subsequently named PRV-1, which is highly expressed in granulocytes from patients with PV (n = 19), but not detectable in normal control granulocytes (n = 21). Moreover, PRV-1 is not expressed in mononuclear cells from patients with chronic myelogenous leukemia (n = 4) or acute myelogenous leukemia (n = 5) or in granulocytes from patients with essential thrombocythemia (n = 4) or secondary erythrocytosis (n = 4). Northern blot analysis showed that PRV-1 is highly expressed in normal human bone marrow and to a much lesser degree in fetal liver. It is not expressed in a variety of other tissues tested. Although PRV-1 is not expressed in resting granulocytes from normal controls, stimulation of these cells with granulocyte colony-stimulating factor induces PRV-1 expression. The PRV-1 cDNA encodes an open reading frame of 437 amino acids, which contains a signal peptide at the N-terminus and a hydrophobic segment at the C-terminus. In addition, PRV-1 contains 2 cysteine-rich domains homologous to those found in the uPAR/Ly6/CD59/snake toxin-receptor superfamily. We therefore propose that PRV-1 represents a novel hematopoietic receptor. (Blood. 2000;95:2569-2576)
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PMID:Cloning of PRV-1, a novel member of the uPAR receptor superfamily, which is overexpressed in polycythemia rubra vera. 1549 66

The cDNA for polycythemia rubra vera 1 (PRV-1), a novel hematopoietic receptor, was recently cloned by virtue of its overexpression in patients with polycythemia vera. PRV-1 is a member of the uPAR/CD59/Ly6 family of cell surface receptors, which share a common cysteine-rich domain and are tethered to the cell surface via a glycosylphosphatidylinositol (GPI) link. We have determined the intron-exon structure of the PRV1 gene and show that the locus is structurally intact in patients with polycythemia vera. Thus, PRV-1 overexpression in these patients is not due to rearrangement or structural alteration of the gene. Northern blot analysis detects multiple PRV-1 transcripts. Here we show that these transcripts arise from alternative polyadenylation and encode the same protein. Biochemical analysis reveals that PRV-1 is N-glycosylated and embedded in the cell membrane by a lipid anchor, like other members of this family. Moreover, PRV-1 is shed from the cell surface because soluble protein can be detected in cell supernatants. Fluorescence-activated cell sorting analysis of stably transfected cells revealed that PRV-1 is recognized by antibodies directed against the neutrophil antigen NB1/CD177. Flow cytometry of bone marrow and peripheral blood of both healthy donors and patients with polycythemia vera showed that PRV-1 protein is expressed on myeloid cells of the granulocytic lineage. However, unlike the significant difference in PRV-1 expression observed on the mRNA level, the amount of PRV-1 protein on the cell surface is not consistently elevated in patients with polycythemia vera compared with healthy controls. Therefore, quantification of PRV-1 surface expression cannot be used for the diagnosis of polycythemia vera.
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PMID:Biochemical characterization of PRV-1, a novel hematopoietic cell surface receptor, which is overexpressed in polycythemia rubra vera. 1223 54

The Philadelphia chromosome-negative chronic myeloproliferative disorders (CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (IMF), have overlapping clinical features but exhibit different natural histories and different therapeutic requirements. Phenotypic mimicry amongst these disorders and between them and nonclonal hematopoietic disorders, lack of clonal diagnostic markers, lack of understanding of their molecular basis and paucity of controlled, prospective therapeutic trials have made the diagnosis and management of PV, ET and IMF difficult. In Section I, Dr. Jerry Spivak introduces current clinical controversies involving the CMPD, in particular the diagnostic challenges. Two new molecular assays may prove useful in the diagnosis and classification of CMPD. In 2000, the overexpression in PV granulocytes of the mRNA for the neutrophil antigen NBI/CD177, a member of the uPAR/Ly6/CD59 family of plasma membrane proteins, was documented. Overexpression of PRV-1 mRNA appeared to be specific for PV since it was not observed in secondary erythrocytosis. At this time, it appears that overexpression of granulocyte PRV-1 in the presence of an elevated red cell mass supports a diagnosis of PV; absence of PRV-1 expression, however, should not be grounds for excluding PV as a diagnostic possibility. Impaired expression of Mpl, the receptor for thrombopoietin, in platelets and megakaryocytes has been first described in PV, but it has also been observed in some patients with ET and IMF. The biologic basis appears to be either alternative splicing of Mpl mRNA or a single nucleotide polymorphism, both of which involve Mpl exon 2 and both of which lead to impaired posttranslational glycosylation and a dominant negative effect on normal Mpl expression. To date, no Mpl DNA structural abnormality or mutation has been identified in PV, ET or IMF. In Section II, Dr. Tiziano Barbui reviews the best clinical evidence for treatment strategy design in PV and ET. Current recommendations for cytoreductive therapy in PV are still largely similar to those at the end of the PVSG era. Phlebotomy to reduce the red cell mass and keep it at a safe level (hematocrit < 45%) remains the cornerstone of treatment. Venesection is an effective and safe therapy and previous concerns about potential side effects, including severe iron deficiency and an increased tendency to thrombosis or myelofibrosis, were erroneous. Many patients require no other therapy for many years. For others, however, poor compliance to phlebotomy or progressive myeloproliferation, as indicated by increasing splenomegaly or very high leukocyte or platelet counts, may call for the introduction of cytoreductive drugs. In ET, the therapeutic trade-off between reducing thrombotic events and increasing the risk of leukemia with the use of cytoreductive drugs should be approached by patient risk stratification. Thrombotic deaths seem very rare in low-risk ET subjects and there are no data indicating that fatalities can be prevented by starting cytoreductive drugs early. Therefore, withholding chemotherapy might be justifiable in young, asymptomatic ET patients with a platelet count below 1500000/mm(3) and with no additional risk factors for thrombosis. If cardiovascular risk factors together with ET are identified (smoking, obesity, hypertension, hyperlipidemia) it is wise to consider platelet-lowering agents on an individual basis. In Section III, Dr. Gianni Tognoni discusses the role of aspirin therapy in PV based on the recently completed European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) Study, a multi-country, multicenter project aimed at describing the natural history of PV as well as the efficacy of low-dose aspirin. Aspirin treatment lowered the risk of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (relative risk 0.41 [95% CI 0.15-1.15], P =.0912). Total and cardiovascular mortality were also reduced by 46% and 59%, respectively. Major bleedings were slightly increased nonsignificnsignificantly by aspirin (relative risk 1.62, 95% CI 0.27-9.71). In Section IV, Dr. Giovanni Barosi reviews our current understanding of the pathophysiology of IMF and, in particular, the contributions of anomalous megakaryocyte proliferation, neoangiogenesis and abnormal CD34(+) stem cell trafficking to disease pathogenesis. The role of newer therapies, such as low-conditioning stem cell transplantation and thalidomide, is discussed in the context of a general treatment strategy for IMF. The results of a Phase II trial of low-dose thalidomide as a single agent in 63 patients with myelofibrosis with meloid metaplasia (MMM) using a dose-escalation design and an overall low dose of the drug (The European Collaboration on MMM) will be presented. Considering only patients who completed 4 weeks of treatment, 31% had a response: this was mostly due to a beneficial effect of thalidomide on patients with transfusion dependent anemia, 39% of whom abolished transfusions, patients with moderate to severe thrombocytopenia, 28% of whom increased their platelet count by more than 50 x 10(9)/L, and patients with the largest splenomegalies, 42% of whom reduced spleen size of more than 2 cm.
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PMID:Chronic myeloproliferative disorders. 1463 83

In Western countries, thrombotic risk factors for Budd-Chiari syndrome (BCS) are very common, including factor V Leiden mutation, prothrombin G20210A mutation, myeloproliferative neoplasms, paroxysmal nocturnal haemoglobinuria, etc. However, the data regarding thrombotic risk factors in Chinese BCS patients are extremely limited. An observational study was conducted to examine this issue. A total of 246 BCS patients who were consecutively admitted to our department between July 1999 and December 2011 were invited to be examined for thrombotic risk factors. Of these, 169 patients were enrolled. Neither factor V Leiden mutation nor prothrombin G20210A mutation was found in any of 136 patients tested. JAK2 V617F mutation was positive in four of 169 patients tested. Neither MPL W515L/K mutation nor JAK2 exon 12 mutation was found in any of 135 patients tested. Overt myeloproliferative neoplasms were diagnosed in five patients (polycythemia vera, n=3; essential thrombocythemia, n=1; idiopathic myelofibrosis, n=1). Two of them had positive JAK2 V617F mutation. Both CD55 and CD59 deficiencies were found in one of 166 patients tested. This patient had a previous history of paroxysmal nocturnal haemo-globinuria before BCS. Anticardiolipin IgG antibodies were positive or weakly positive in six of 166 patients tested. Hyperhomocysteinaemia was found in 64 of 128 patients tested. 5,10-methylenetetrahydrofolate reductase C677T mutation was found in 96 of 135 patients tested. In conclusion, factor V Leiden mutation, prothrombin G20210A mutation, myeloproliferative neoplasms, and paroxysmal nocturnal haemoglobinuria are very rare in Chinese BCS patients, suggesting that the etiological distribution of BCS might be different between Western countries and China.
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PMID:Thrombotic risk factors in Chinese Budd-Chiari syndrome patients. An observational study with a systematic review of the literature. 2344 59