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 rare, progressive myeloproliferative disorder thought to originate from the clonal expansion of a multipotent haemopoietic stem cell. This disease is characterised by hyperproliferation of the erythroid, myeloid and megakaryocyte lineages in the early phase, anaemia and fibrosis in the spent phase, and with a significant number of patients developing acute myeloid leukaemia (AML) in the final phase. Studies investigating the growth factor requirements of committed progenitors have shown hypersensitivity to a number of haemopoietic growth factors (HGF) in vitro and several HGF receptor and signalling molecule alterations have been reported. The findings to date, however, are unable to account for the transformation of a primitive stem cell and the many alterations to growth factor responses seen in PV progenitors. Identification of the primary lesion that leads to the pathogenesis of PV is of major importance given the profound effects on regulation of the haemopoietic stem cell compartment. In this article we focus on characteristics of the disease, research findings to date and possible mechanisms to explain altered growth factor responses, receptor alterations and signalling abnormalities in PV.
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PMID:Molecular aspects of polycythemia vera (review). 1093 84

The V617F activating mutation of janus kinase 2 (JAK2), a kinase essential for cytokine signalling, characterizes Polycythemia vera (PV), one of the myeloproliferative neoplasms (MPN). However, not all MPNs carry mutations of JAK2, and in JAK2-mutated patients, expression of JAK2V617F does not always result in clone expansion. In the present study, we provide evidence that inflammation-linked cytokines are required for the growth of JAK2V617F-mutated erythroid progenitors. In a first series of experiments, we searched for cytokines over-expressed in PV using cytokine antibody (Ab) arrays, and enzyme-linked immunosorbent assays for analyses of serum and bone marrow (BM) plasma, and quantitative reverse transcription-PCRs for analyses of cells purified from PV patients and controls. We found that PV patients over-expressed anti-inflammatory hepatocyte growth factor (HGF) and interleukin-11 (IL-11), BM mesenchymal stromal cells (BMMSCs) and erythroblasts being the main producers. In a second series of experiments, autocrine/paracrine cytokine stimulation of erythroblasts was blocked using neutralizing Abs specific for IL-11 or c-MET, the HGF receptor. The growth of JAK2V617F-mutated HEL cells and PV erythroblasts was inhibited, indicating that JAK2-mutated cells depend on HGF and IL-11 for their growth. Additional experiments showed that transient expression of JAK2V617F in BaF-3/erythropoietin receptor cells, and invalidation of JAK2V617F in HEL cells using anti-JAK2 small interfering RNA, did not affect HGF and IL-11 expression. Thus, anti-inflammatory HGF and IL-11 are upregulated in PV and their overproduction is not a consequence of JAK2V617F. As both cytokines contribute to the proliferation of PV erythroblasts, blocking the c-MET/HGF/IL-11 pathways could be of interest as an additional therapeutic option in PV.
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PMID:Anti-inflammatory cytokines hepatocyte growth factor and interleukin-11 are over-expressed in Polycythemia vera and contribute to the growth of clonal erythroblasts independently of JAK2V617F. 2104 81