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)

Polycythaemia vera (PV) patients' blood burst-forming units-erythroid (BFU-E) have an enhanced sensitivity to stem cell factor (SCF) compared to normal BFU-E. To characterize SCF receptors on erythroid progenitors from normal individuals and PV patients, we performed binding experiments using radioiodinated recombinant SCF (rSCF), day 1 BFU-E and day 8 erythroid colony-forming cells (ECFC), which are mostly colony-forming units-erythroid (CFU-E). 125I-rSCF binds to a single class of cell surface receptors (23,000/ECFC) at 0 degrees C with a high-binding affinity (Kd = 17 pM). Saturation occurred at 0.5 nM (10 ng/ml) which produces a nearly maximum biological effect. One half of the radiolabelled rSCF was internalized by the cells after 30 min at 37 degrees C. No significant differences in the receptor number, dissociation constant, or internalization rate were found between normal and PV ECFC. Autoradiographic analysis of 125I-rSCF binding to normal BFU-E and ECFC showed that no differences were present in either the percentage of positive cells or the number of radioactive grains/cell between the normal and PV erythroid progenitors. The enhanced sensitivity of PV BFU-E and CFU-E to SCF does not appear to be related to changes in SCF receptor number, binding affinity or internalization and the hypersensitivity of PV erythroid progenitors to SCF must reside in a further internal cellular abnormality.
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PMID:Polycythaemia vera. IV. Specific binding of stem cell factor to normal and polycythaemia vera highly purified erythroid progenitor cells. 752 30

We evaluated the effects of transforming growth factor-beta 1 (TGF-beta 1) on the growth of hematopoietic progenitors in normal donors and in patients with hematologic malignancies now designed as clonal disorders of multipotential stem cells. TGF-beta 1 at 80 pM exhibited differential effects on the normal hematopoietic progenitors when cells were stimulated with different growth factors, such as G-CSF, GM-CSF, interleukin-3 (IL-3), or stem cell factor (SCF). The suppressive effect by TGF-beta 1 was increased for growth with GM-CSF, IL-3, and SCF, and growth with G-CSF was unaffected in hematologic malignancies, TGF-beta 1 suppression for growth with G-CSF was increased for essential thrombocythemia (ET) and polycythemia vera; chronic myelogenous leukemia (CML) in chronic phase; CML in accelerated phase; CML in myeloid crisis; myelodysplastic syndrome (MDS) in refractory anemia; MDS in refractory anemia with an excess of blasts; and acute myeloblastic leukemia (AML). In CML-myeloid crisis and AML, TGF-beta 1 almost completely abolished the growth, with some patient-to-patient variation. The mean ED50s for the growth of leukemic blast progenitors were 1.6, 1.2, 0.7, and 0.2 pM in the presence of G-CSF, GM-CSF, IL-3, and SCF, respectively, c-myc and c-myb antisense oligonucleotides significantly suppressed the growth of leukemic blast progenitors, but not that of clonogenic cells from normal donors and patients with ET. We also demonstrated that TGF-beta 1 inhibits mRNA expression by AML blasts for c-myc and/or c-myb. When the data are taken together, growth suppression by TGF-beta 1 appears to increase with the progression of clonal evolution in hematologic malignancies.
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PMID:Differential effects of TGF-beta 1 on normal and leukemic human hematopoietic cell proliferation. 754 18

"Autonomous" development of erythroid colonies in erythropoietin (EPO)-free semi-solid culture has been used as an in vitro assay for diagnosis of polycythemia vera (PV). These colonies, however, are small and poorly hemoglobinized, rendering the assay in many cases unreliable. We report here on the use of a novel assay; it combines a modified culture procedure that maximizes the growth of EPO-independent erythroid cells, and immunofluorescence flow cytometry for their detection and quantitation. Peripheral blood mononuclear cells are cultured for 2-5 days in the presence of a combination of growth factors. During this phase, early erythroid committed progenitors, burst forming units (BFUe), proliferate and differentiate into colony forming units (CFUe)-like progenitors. In the second phase, the latter cells, in the presence of stem cell factor, hemin, and iron-saturated transferrin, continue to proliferate and mature into hemoglobin (Hb)-containing orthochromatic normoblasts. Neither phases contained EPO. The culture produced large, pure, and synchronized erythroid cell populations. The cells were then dually labeled with fluorescent probes, nuclear DNA with thiazole orange and intracellular hemoglobin (Hb) with phycoerythrin-conjugated monoclonal antibodies against human Hb. Cells positive for both labels were assigned as Hb-containing nucleated precursors. The presence of such cells in EPO-free cultures indicated "autonomous growth." None of the EPO-free cultures derived from normal donors or patients with secondary polycythemia contained such cells. Cultures derived from PV patients contained from 5 to 92% "autonomously grown" cells. These culture and analysis methods should minimize false negative results with PV patients and provide objective and quantitative data.
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PMID:Improved method for diagnosis of polycythemia vera based on flow cytometric analysis of autonomous growth of erythroid precursors in liquid culture. 898 Feb 60

Erythropoietin (EP) and stem cell factor (SCF) are essential growth factors for erythroid progenitor cell proliferation and differentiation in serum-free culture. It has been previously shown that burst-forming units-erythroid and colony-forming units-erythroid from patients with polycythemia vera (PV) have enhanced sensitivity to EP and SCF compared with normal erythroid progenitors, but little is known about the mechanism for this difference. In the present investigation, the effect of EP and SCF on protein tyrosine phosphorylation in day-8 normal and PV erythroid colony-forming cells, which give rise to colonies of 2-49 hemoglobinized cells, was studied. EP rapidly induced tyrosine phosphorylation of the EP receptor, whereas the most prominent phosphorylated protein induced by SCF was identified as the SCF receptor. No additional phosphorylated proteins were evident when PV cells were compared with normal cells. Culture of normal erythroid progenitors with orthovanadate, an inhibitor of protein tyrosine phosphatases, resulted in an increased number of erythroid colonies and enhanced protein tyrosine phosphorylation. However, in contrast, little enhancement was evident with PV cells. These results indicate that, although vanadate may be acting in normal erythroid progenitors as a phosphatase inhibitor that potentiates the kinase activity induced by SCF and EP, this function is diminished in PV cells. Because erythropoiesis is regulated by a balance between protein tyrosine kinase activity and protein tyrosine phosphatase activity, PV patients may have an abnormal phosphatase activity allowing increased cell proliferation.
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PMID:Polycythemia vera. V. Enhanced proliferation and phosphorylation due to vanadate are diminished in polycythemia vera erythroid progenitor cells: a possible defect of phosphatase activity in polycythemia vera. 916 Jun 62

Polycythaemia vera (PV) is a myeloproliferative disorder characterized by haematopoietic progenitor cells being hypersensitive to cytokines such as erythropoietin, interleukin-3, stem cell factor and insulin-like growth factor 1, which results in an increased production of mature blood cells. The pathogenetic cellular mechanism(s) behind this hypersensitivity to cytokines is unknown, but the number of cytokine receptors and the interaction between ligand and receptor are normal in PV. Interest has therefore focused on post-receptor mechanism(s). Haematopoietic cell phosphatase (HCP) is an intracellular tyrosine phosphatase that has been demonstrated to regulate proliferative signals negatively induced by the cytokines mentioned above. Moreover, motheaten mice that genetically lack HCP have an increased amount of erythroid progenitors that are hypersensitive to Epo, and patients with familial polycythaemia have been shown to exhibit a mutation of the Epo receptor gene that includes the docking site for HCP. We therefore studied mRNA expression of HCP in pure populations of CD34+ cells, granulocytes, platelets and lymphocytes from patients with PV, chronic myeloid leukaemia (CML) or essential thrombocythemia (ET), as well as healthy controls. Using a polymerase chain reaction analysis employing specific primers for HCP, we failed to detect any abnormalities of HCP expression in PV in any of the cell populations that were examined. Moreover, HCP mRNA expression was similar in ET and CML compared to controls. Finally, Western blot analysis revealed a normal HCP protein content in PV granulocytes and platelets. We therefore conclude that neither an impaired expression of the HCP gene nor a defect in HCP protein synthesis is present in PV, and does not seem to play a role in the aetiology of this disorder.
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PMID:No evidence for an altered mRNA expression or protein level of haematopoietic cell phosphatase in CD34+ bone marrow progenitor cells or mature peripheral blood cells in polycythaemia vera. 941 43

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

The SHP-1 phosphatase associates with the receptors for erythropoietin, stem cell factor, and interleukin-3, and negatively regulates the mitogenic signals generated during engagement by their respective ligands. The erythroid progenitors of patients with polycythemia vera are hypersensitive to the mitogenic effects of these growth factors despite the fact that the numbers and binding affinities for their receptors are not increased. To determine whether post-receptor signaling defects may account for growth factor-hypersensitivity in polycythemia vera, we determined the expression of SHP-1 in highly purified erythroid progenitors from polycythemia vera patients. Our data demonstrate that in approximately 60% of the patients, expression of SHP-1 in the colony forming unit-erythroid population is diminished. The decreased expression of the protein may result from a transcriptional defect, as suggested by the diminished SHP-1 mRNA expression in the erythroid progenitors of these patients. Studies to determine the level of maturation of polycythemia vera and normal cells indicated that there was no difference between the two at early colony forming unit-erythroid stage of differentiation although polycythemia vera cells showed retarded differentiation kinetics at late colony forming unit-erythroid stage of differentiation. Furthermore, SHP-1 expression in normal colony forming unit-erythroid demonstrated downregulation of mRNA and protein levels during terminal differentiation, suggesting that its function is required for growth control during the early stages of erythropoiesis. These results indicate an important role for SHP-1 in the regulation of normal human erythroid progenitors and suggest that defective expression of the protein may contribute to the pathogenesis of polycythemia vera.
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PMID:Defective expression of the SHP-1 phosphatase in polycythemia vera. 1039 Jan 87

Polycythemia vera (PV) is a myeloproliferative disorder arising in a multipotent hematopoietic stem cell. The pathogenesis of PV remains poorly understood; however, the biologic hallmark of this disease is the presence of erythropoietin (Epo)-independent colony formation (endogenous erythroid colony [EEC]) and cytokine hypersensitivity. We have developed a simple liquid culture from CD34+ cells to study PV erythroid differentiation. PV erythroid differentiation was characterized in this culture system by two types of abnormalities: 1) an increased proliferation of progenitors in response to cytokines, associated with strict cytokine dependency for preventing apoptosis; and 2) Epo-independent terminal erythroid differentiation in the presence of stem cell factor and interleukin-3 as evidenced by the acquisition of glycophorin A. The level of Epo-independent terminal differentiation correlates in PV patients with the number of EEC. Epo-independent terminal differentiation as well as normal Epo-induced differentiation were repressed by inhibitors of JAK2 (AG490), PI3K (LY294002), and the Src family kinases (PP2). In contrast, an inhibitor of the ERK/MAP kinase pathway (PD98059) had no effect on Epo-independent terminal differentiation. These signaling abnormalities were not mediated by a decreased expression or activity of the membrane tyrosine phosphatase CD45, which dephosphorylates JAK2 and Src family kinases. This study demonstrates that early steps of PV erythroid differentiation are strictly cytokine dependent. In contrast, late erythroid differentiation is an Epo-independent phenomenon that is mediated by signaling pathways identical to those in Epo-induced differentiation.
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PMID:Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera. 1510 79

Imatinib mesylate is a small molecule drug that in vitro inhibits the Abelson (Abl), Arg (abl-related gene), stem cell factor receptor (Kit), and platelet-derived growth factor receptor A and B (PDGFRA and PDGFRB) tyrosine kinases. The drug has acquired therapeutic relevance because of similar inhibitory activity against certain activating mutations of these molecular targets. The archetypical disease in this regard is chronic myeloid leukemia, where abl is constitutively activated by fusion with the bcr gene (bcr/abl). Similarly, the drug has now been shown to display equally impressive therapeutic activity in eosinophilia-associated chronic myeloproliferative disorders that are characterized by activating mutations of either the PDGFRB or the PDGFRA gene. The former usually results from translocations involving chromosome 5q31-33, and the latter usually results from an interstitial deletion involving chromosome 4q12 (FIP1L1-PDGFRA). In contrast, imatinib is ineffective, in vitro and in vivo, against the mastocytosis-associated c-kit D816V mutation. However, wild-type and other c-kit mutations might be vulnerable to the drug, as has been the case in gastrointestinal stomal cell tumors. Imatinib is considered investigational for the treatment of hematologic malignancies without a defined molecular drug target, such as polycythemia vera, myelofibrosis with myeloid metaplasia, and acute myeloid leukemia.
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PMID:Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders. 1516 33

In order to investigate the biologic processes underlying and resulting from the megakaryocytic hyperplasia that characterizes idiopathic myelofibrosis (IMF), peripheral blood CD34+ cells isolated from patients with IMF, polycythemia vera (PV), and G-CSF-mobilized healthy volunteers were cultured in the presence of stem cell factor and thrombopoietin. IMF CD34+ cells generated 24-fold greater numbers of megakaryocytes (MKs) than normal CD34+ cells. IMF MKs were also shown to have a delayed pattern of apoptosis and to overexpress the antiapoptotic protein bcl-xL. MK hyperplasia in IMF is, therefore, likely a consequence of both the increased ability of IMF progenitor cells to generate MKs and a decreased rate of MK apoptosis. Media conditioned (CM) by CD61+ cells generated in vitro from CD34+ cells were then assayed for the levels of growth factors and proteases. Higher levels of transforming growth factor-beta (TGF-beta) and active matrix metalloproteinase-9 (MMP9) were observed in media conditioned with IMF CD61+ cells than normal or PV CD61+ cells. Both normal and IMF CD61+ cells produced similar levels of VEGF. MK-derived TGF-B and MMP-9, therefore, likely contribute to the development of many pathological epiphenomena associated with IMF.
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PMID:Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis. 1791 55


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