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

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.
 ...
PMID:Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera. 1510 79

Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by excessive erythrocyte production. Most patients with PV harbor an activating JAK2 mutation, but the molecular links between this mutation and erythrocyte overproduction are unknown. The interaction between death receptors and their ligands contributes to the physiological regulation of erythropoiesis through the inhibition of erythroblast proliferation and differentiation. With the use of an in vitro culture system to generate differentiating erythroid cells, we found that erythroblasts derived from patients with PV harboring the JAK2 V617F mutation were able to proliferate and generate higher numbers of mature erythroid cells in the presence of inhibitory signals delivered by CD95 (Fas/Apo-1) and TRAIL receptor stimulation. JAK2-mutated PV erythroblasts showed lower levels of CD95-induced caspase activation and incomplete caspase-mediated cleavage of the erythroid transcription factor GATA-1, which was entirely degraded in normal erythroblasts on CD95 stimulation. JAK2 mutation was associated in PV erythroblasts with cytokine-independent activation of the JAK2 effectors Akt/PKB and ERK/MAP and with a deregulated expression of c-FLIP(short), a potent cellular inhibitor of death receptor-induced apoptosis. These results show the presence in PV erythroblasts of proliferative and antiapoptotic signals that may link the JAK2 V617F mutation with the inhibition of death receptor signaling, possibly contributing to a deregulation of erythropoiesis.
 ...
PMID:Increased death receptor resistance and FLIPshort expression in polycythemia vera erythroid precursor cells. 1638 30

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic progenitor cell disorders characterized by the proliferation of one or more hematopoietic lineages. The classical MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) entities. These disorders are characterized by bone marrow morphology typical for each disease, and by the presence of JAK2V617F mutation in the marrow and blood. However, JAK2V617F cannot account for the phenotypic heterogeneity of MPNs because approximately half of all cases of ET and PMF show no evidence of this molecular marker. Therefore, the search for novel markers of these diseases is necessary to improve pathomorphological and molecular diagnostics. This study aimed to investigate the changes in expression patterns of the proteins STAT5 (the signal transducers and activators of transcription 5) and ERK (extracellular signal-regulated kinase) in bone marrow trephine specimens, derived both from patients with wild-type and mutant (V617F) forms of JAK2 kinase. Furthermore, the changes in STAT5 and ERK2 gene expression levels in the same patients were also investigated. The results of our immunohistochemical, immunoblotting and RT-qPCR studies revealed at least four major unique features of three types of MPNs. These include: i) more pronounced expression of phosphoSTAT5 protein in patients with JAK2V617F mutation compared to patients with wild-type of JAK2 kinase ii) different expression pattern of pSTAT5 in the nucleus and the cytoplasm of megakaryocytes and other bone marrow cells; iii) approximately 5-fold higher expression level of STAT5a gene in PV in comparison to patients with PMF and approximately 2-fold higher than in ET patients; iv) different, intracellular expression patterns of ERK2 and ERK1/2 antigens allowed to distinguish each subtype of MPN. These abnormalities in expression patterns of STAT5 and ERK proteins and genes provide some novel molecular features of MPNs and brings us closer to explaining the pathogenesis of MPNs.
 ...
PMID:pSTAT5 and ERK exhibit different expression in myeloproliferative neoplasms. 2826 27