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)

We developed a sensitive method of measurement of granulocyte colony-stimulating factor (G-CSF) by an enzyme-linked immunosorbent assay, which we applied in the plasma of the bone marrow aspirate in 70 patients with various hematological disorders. The lowest limit of detection by this method is 2 pg/ml. G-CSF was detected in all but two of the patients. Compared to the G-CSF level in normal healthy controls, those in non-Hodgkin's malignant lymphoma, aplastic anemia, agranulocytosis and multiple myeloma were significantly higher, while the level in refractory anemia was not different. The G-CSF level in acute myelogenous leukemia patients was either elevated or decreased regardless of the French-American-British subgroup. The level in acute lymphoblastic leukemia was not different from the normal value, as was that in refractory anemia with an excess of blasts, and that in chronic lymphocytic leukemia. A patient with chronic myelomonocytic leukemia showed initial elevation of G-CSF with normalization after entering complete remission. The G-CSF level in chronic myelogenous leukemia was significantly decreased, although one patient in hematological remission who was under alpha-interferon therapy showed normal levels. The level in polycythemia vera was not significantly different from the normal value. The G-CSF level for the entire group showed an inverse, although not statistically significant, correlation with the percentages of myeloid cells of the bone marrow (r = -0.174, p = 0.1703, n = 80). These results are thought to reflect the regulatory mechanism of granulopoiesis in the bone marrow in various hematological disorders, and it is concluded that this method may be of clinical use in the treatment of patients with these disorders and in the selection of candidates likely to benefit from G-CSF administration.
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PMID:The levels of granulocyte colony-stimulating factor in the plasma of the bone marrow aspirate in various hematological disorders. 872 2

In hematological diseases such as myeloproliferative disorders (MPD) or myelodysplastic syndromes (MDS), some abnormalities in the chemiluminescence of neutrophils are observed. There are two groups; one includes chronic myelogenous leukemia (CML), essential thrombocythemia (ET) and MDS, which all have decreased chemiluminescence of neutrophils. The other group includes polycythemia vera (PV) which has increased neutrophil chemiluminescence. We studied the neutrophil function by analyzing the chemiluminescence in 35 patients with hematological diseases. In most of these cases the defects in chemiluminescence in 35 patients with hematological diseases. In most of these cases the defects in chemiluminescence in response to N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) were correlated with those in response to phorbol 12-myristate 13-acetate (PMA). But there were exceptional cases in which the maximal light emission of chemiluminescence (Max CL) in response to FMLP was obviously lower than controls despite the fact that the Max CL in response to PMA was the same as the controls. These facts suggest a heterogenicity of the defect site in these diseases. There was a correlation between the level of chemiluminescence and the neutrophil alkaline phosphatase (NAP) activity in these patients. In vitro culture of CML neutrophils with granulocyte colony-stimulating factor (G-CSF) showed a correlation between the increase in the level of chemiluminescence and NAP activity. These results suggest that NAP may take part in the control of neutrophil function.
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PMID:Chemiluminescence of neutrophils in patients with myeloproliferative or myelodysplastic hematologic diseases--relation to neutrophil alkaline phosphatase activity. 768 68

The neutrophil superoxide (O2-)-producing capacity in 57 patients with chronic myeloproliferative disorders (MPDs) and eight patients with chronic myelomonocytic leukemia (CMML) was investigated. O2- release in neutrophils stimulated by chemotactic peptide was markedly increased in all types of chronic MPD, including chronic myelogenous leukemia in both chronic phase and blastic crisis, polycythemia vera, and essential thrombocythemia, but was normal in CMML, which is thought to be a myelodysplastic disorder rather than MPD. Increase in O2(-)-producing capacity in MPD was also observed when other receptor-mediated agonists such as interleukin-8 and concanavalin A were used, but not when phorbol ester, a direct activator of protein kinase C, was used as the triggering agonist of O2- release. Priming effects of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), and tumor necrosis factor (TNF) on chemotactic peptide-induced O2- release was observed in all patients with MPD and CMML, though fold enhancement of priming effects was much less in MPD compared with normal subjects. In addition, the priming effects of TNF were less than those of GM-CSF in 10 cases, whereas the priming effects of TNF were consistently and markedly greater than those of GM-CSF in normal subjects. Tyrosine phosphorylation of 42-kDa protein stimulated by G-CSF, GM-CSF, and TNF was observed in CML neutrophils to be identical to that in normal neutrophils. Present results indicate specific potentiation of the receptor-mediated route of signaling that is linked to the respiratory burst and downregulated responsiveness to cytokines in neutrophils in patients with all types of chronic MPD, suggesting in vivo priming of patient neutrophils via certain mechanism by cytokines or related stimuli in these hematological disorders.
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PMID:Increased neutrophil respiratory burst in myeloproliferative disorders: selective enhancement of superoxide release triggered by receptor-mediated agonists and low responsiveness to in vitro cytokine stimulation. 898 3

In polycythemia vera (PV) erythroid colonies that grow in vitro in the absence of exogenous erythropoietin (EPO) arise from the abnormal clone that is responsible for overproduction of red blood cells. Although the mechanism of autonomous formation of burst-forming units-erythroid (BFU-E) is not fully understood, a spontaneous release of growth regulatory molecules by PV cells and/or by accessory cells is likely to be involved. Because of its cytokine synthesis inhibiting action, interleukin-10 (IL-10) could be a potentially useful molecule to modulate abnormal erythropoiesis in PV. We studied the effect of recombinant human IL-10 on the EPO-independent growth of erythroid bursts derived from peripheral blood mononuclear cells (PBMNCs) of patients with PV. IL-10 showed a profound, dose-dependent, and specific inhibitory effect on autonomous BFU-E formation. Ten nanograms per milliliter of IL-10 significantly suppressed spontaneous growth of erythroid colonies in methylcellulose in five of five PV patients tested with a mean inhibition by 81% (range, 72-94). To elucidate the possible mechanism of the inhibitory action of IL-10 we further studied the effect of anticytokine antibodies on autonomous BFU-E growth and the ability of exogenous cytokines to restore IL-10-induced suppression of erythroid colony growth. Among a panel of growth regulatory factors tested (granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-3, granulocyte colony-stimulating factor, stem cell factor, and insulin-like growth factor-1) GM-CSF was the only molecule for which both an inhibition of spontaneous BFU-E formation by its respective antibody as well as a significant restimulation of erythroid colonies in IL-10-treated cultures by exogenous addition was found. Moreover, inhibition of GM-CSF production by IL-10 was shown in PV PBMNCs at the mRNA level. Our data indicate that autonomous BFU-E growth in PV can be profoundly inhibited by IL-10 and that this inhibitory effect seems to be at least in part secondary to suppression of endogenous GM-CSF production.
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PMID:Interleukin-10 inhibits erythropoietin-independent growth of erythroid bursts in patients with polycythemia vera. 973 Oct 54

We studied telomerase regulation and telomere length in hematopoietic progenitor cells from peripheral blood and bone marrow from patients with acute and chronic leukemia and myeloproliferative diseases. CD34+ cells from a total of 93 patients with either acute myeloid leukemia (AML; n = 25), chronic myeloid leukemia (CML; n = 21), chronic lymphocytic leukemia (CLL; n = 18), polycythemia vera (PV; n = 16), or myelodysplastic syndromes (MDS; n = 13) were analyzed before and in 19 patients after ex vivo expansion in the presence of multiple cytokines (kit ligand, interleukin-3, interleukin-6, and granulocyte colony-stimulating factor plus erythropoietin). Compared with hematopoietic progenitor cells from normal donors (n = 108), telomerase activity (TA) was increased 2- to 5-fold in chronic phase (CP)-CML, CLL, PV, and MDS. In AML, accelerated phase (AP) and blastic phase (BP)-CML, basal TA was 10- to 50-fold higher than normal. TA of CP-CML CD34+ cells was up-regulated within 72 h of ex vivo culture, peaked after 1 week, and decreased below detection after 2 weeks. In contrast, TA in AP/BP-CML and AML CD34+ cells was down-regulated after 1 week of culture and decreased further thereafter. The expansion potential of CD34+ cells from patients with leukemia was considerably decreased compared with CD34+ cells from normal donors. The average expansion of cells from leukemic individuals was 6.5-, 2.3-, 0.6-, and 0.2-fold in weeks 1, 2, 3, and 4, respectively, whereas expansion of normal cells was 5- to 15-fold higher. In serial expansion culture, a median telomeric loss of 0.7 kbp was observed during 3-4 weeks of expansion. Our results demonstrate that up-regulation of telomerase is similar in CD34+ cells from CP-CML, CLL, PV, and MDS patients and in normal hematopoietic cells during the first week of culture, whereas in AML and AP/BP-CML, telomerase is high at baseline and down-regulated during expansion culture. High levels of telomerase in leukemic progenitors at baseline may be a feature of both the malignant phenotype and rapid cycling. Telomerase down-regulation during culture of leukemic cells may be due to the decreased expansion potential or repression of normal hematopoiesis, or in AML it may be due to the partial differentiation of AML cells, shown previously to be associated with loss of TA. Telomere shortening during ex vivo expansion correlated with low levels of TA, particularly in chronic leukemic and MDS progenitors where telomerase was insufficient to protect against telomere bp loss during intense proliferation.
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PMID:Telomerase activity and telomere length in acute and chronic leukemia, pre- and post-ex vivo culture. 1067 44

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

We identified 13 new gene expression markers that were elevated and one marker, ANKRD15, that was down-regulated in patients with polycythemia vera (PV). These 14 markers, as well as the previously described PRV1 and NF-E2, exhibited the same gene expression alterations also in patients with exogenously activated granulocytes due to sepsis or granulocyte colony-stimulating factor (G-CSF) treatment. The recently described V617F mutation in the Janus kinase 2 (JAK2) gene allows defining subclasses of patients with myeloproliferative disorders based on the JAK2 genotype. Patients with PV who were homozygous or heterozygous for JAK2-V617F exhibited higher levels of expression of the 13 new markers, PRV1, and NF-E2 than patients without JAK2-V617F, whereas ANKRD15 was down-regulated in these patients. Our results suggest that the alterations in expression of the markers studied are due to the activation of the Jak/signal transducer and activator of transcription (STAT) pathway through exogenous stimuli (sepsis or G-CSF treatment), or endogenously through the JAK2-V617F mutation.
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PMID:Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2. 1608 84

We studied the relationship between granulocyte JAK2 (V617F) mutation status, circulating CD34(+) cells, and granulocyte activation in myeloproliferative disorders. Quantitative allele-specific polymerase chain reaction (PCR) showed significant differences between various disorders with respect to either the proportion of positive patients (53%-100%) or that of mutant alleles, which overall ranged from 1% to 100%. In polycythemia vera, JAK2 (V617F) was detected in 23 of 25 subjects at diagnosis and in 16 of 16 patients whose disease had evolved into myelofibrosis; median percentages of mutant alleles in these subgroups were significantly different (32% versus 95%, P < .001). Circulating CD34(+) cell counts were variably elevated and associated with disease category and JAK2 (V617F) mutation status. Most patients had granulocyte activation patterns similar to those induced by administration of granulocyte colony-stimulating factor. A JAK2 (V617F) gene dosage effect on both CD34(+) cell counts and granulocyte activation was clearly demonstrated in polycythemia vera, where abnormal patterns were mainly found in patients carrying more than 50% mutant alleles. These observations suggest that JAK2 (V617F) may constitutively activate granulocytes and by this means mobilize CD34(+) cells. This exemplifies a novel paradigm in which a somatic gain-of-function mutation is initially responsible for clonal expansion of hematopoietic cells and later for their abnormal trafficking via an activated cell progeny.
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PMID:Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. 1637 57

The JAK2(V617F) mutation is present in almost all patients with polycythemia vera (PV), large proportions of patients with essential thrombocythemia and idiopathic myelofibrosis, and less frequently in atypical myeloproliferative disorders (MPD). We show that transplantation of JAK2(V617F)-transduced bone marrow into BALB/c mice induces MPD reminiscent of human PV, characterized by erythrocytosis, granulocytosis, extramedullary hematopoiesis, and bone marrow fibrosis, but not thrombocytosis. Fluorescence-activated cell sorting of bone marrow and spleen showed proportional expansion of common myeloid progenitors, granulocyte-monocyte and megakaryocyte-erythrocyte progenitors. Megakaryocyte and late erythroid progenitors were dramatically increased, with only modest expansion of early erythroid progenitors. Erythropoietin (Epo) receptor expression was reduced on early, but normal on late erythroblasts. Serum levels of Epo and granulocyte colony-stimulating factor, but not granulocyte macrophage colony-stimulating factor, were reduced, whereas tumor necrosis factor-alpha was increased, possibly exerting a negative effect on JAK2(V617F)-negative hematopoiesis. These data suggest that erythrocytosis and granulocytosis in JAK2(V617F) mice are the net result of a complex interplay between cell intrinsic and extrinsic factors. There were no thromboembolic events and no animals succumbed to their disease, implicating additional factors in the manifestation of human disease. The disease was not transplantable and prolonged observation showed normalization of blood counts in most JAK2(V617F) mice, suggesting that the mutation may not confer self-renewal capacity.
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PMID:Characterization of murine JAK2V617F-positive myeloproliferative disease. 1714 59

JAK2V617F is an acquired mutation associated with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). We tested the hypothesis that the paradox of a single disease allele associated with 3 distinctive clinical phenotypes could be explained in part by host-modifying influences. We screened for genetic variation within 4 candidate genes involved in JAK-STAT signaling, including receptors for erythropoietin (EPOR), thrombopoietin (MPL), and granulocyte colony-stimulating factor (GCSFR), and JAK2. We genotyped 32 linkage disequilibrium tag single nucleotide polymorphism (SNP) loci in 179 white patients: 84 had PV, 58 had PMF, and 37 had ET. Genotype-phenotype analysis showed 3 JAK2 SNPs (rs7046736, rs10815148, and rs12342421) to be significantly but reciprocally associated with PV (P < .001 for all; odds ratio = 0.16, 2.72, and 2.46, respectively) and ET (P < .001 for all; odds ratio = 3.05, 0.29, and 0.30, respectively) but not with PMF. Three additional JAK2 SNPs (rs10758669, rs3808850, and rs10974947) and a single EPOR SNP (rs318699) were also significantly associated with PV but not with ET or PMF. Finally, intragene haplotypes in JAK2 were significantly associated with PV only. Thus, host genetic variation may contribute to phenotypic diversity among myeloproliferative disorders, including in the presence of a shared disease allele.
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PMID:Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders. 1800 99


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