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.
The clinical course of Cystic Fibrosis is characterized by recurrent pulmonary infections which ultimately lead to death by respiratory failure. The most common CF causing mutation, deltaF508-CFTR, produces an incorrectly folded protein, which accumulates within the endoplasmic reticulum. However, the molecular mechanism by which the deltaF508-CFTR protein facilitates pulmonary infection and inflammation remains unclear. Here we show that the expression of deltaF508-CFTR causes a constitutive activation of the pro-inflammatory transcription factor NF-kappaB by eliciting an ER stress reaction, the ER-overload response. This endogenous NF-kappaB activation stimulates the transcription of pro-inflammatory cytokines thereby commencing an inflammatory cascade within the CF lung.
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