Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038002 (splenomegaly)
 9,873 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erythropoietin (Epo) is the major regulator of erythroid viability, proliferation, and differentiation. These functions are transduced following binding of Epo to a specific cell surface receptor, the erythropoietin receptor (EpoR), a member of a new cytokine receptor superfamily of receptors. An activating mutation in the murine EpoR has been described (cEpoR) and confers growth factor-independent growth upon an IL-3-dependent pro-B cell. To determine the effect of an activating mutation in the EpoR upon erythropoiesis specifically and hematopoiesis generally, we infected hematopoietic progenitors and mice with a recombinant erythroleukemic spleen focus-forming virus (SFFV), lacking its pathogenic env gene but expressing cEpoR (SFFVcEpoR). In vitro, infection with SFFVcEpoR resulted in factor-independent growth and development of CFU-Es yet had no effect on BFU-E growth, mixed colony growth, or myeloid colony growth. Mice infected with SFFVcEpoR, but not a virus expressing wild type EpoR (SFFVEpoR), developed erythrocytosis and splenomegaly.
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PMID:Mutation in murine erythropoietin receptor induces erythropoietin-independent erythroid proliferation in vitro, polycythemia in vivo. 131 65

A point mutation at codon 129 of the murine erythropoietin receptor (cEpoR) results in constitutive activation. We have generated a recombinant spleen focus-forming retrovirus in which the env gene is replaced by the cEpoR cDNA. Mice infected with this virus (but not by viruses expressing the wild-type EpoR) develop erythrocytosis and splenomegaly. From the spleen of infected animals we have isolated clonal, growth factor-independent, proerythroblast cell lines that express cEpoR, do not express the putative oncogene spi-1, and have rearranged and inactivated expression of the p53 suppressor oncogene. These cells induce erythroleukemia upon injection into mice. This demonstrates that oncogenic point mutations exist in a member of the cytokine receptor superfamily. The activated erythropoietin receptor does not transform cultured fibroblasts, suggesting why oncogenic mutations in other members of this receptor superfamily have not been detected.
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PMID:An activating mutation in the murine erythropoietin receptor induces erythroleukemia in mice: a cytokine receptor superfamily oncogene. 166 16

Recent evidence suggests that interactions between spleen focus-forming virus (SFFV) env products and the erythropoietin receptor (EpoR) are responsible for viral pathogenicity. Infection of factor-dependent cell lines expressing epoR (the cloned gene for EpoR) with SFFVP is mitogenic, generating cell lines that are no longer dependent on added growth factor, and an immunoprecipitable complex between EpoR and immature env protein in the endoplasmic reticulum has been identified. The dependence of these in vitro activities on env protein processing and their relationship to pathogenicity of SFFV were explored by using glycosylation site mutants of SFFV env. Mutants carrying Asn-->Asp mutations at each of the two consensus signals for N-linked glycosylation in the N-terminal domain of SFFVAP-L env (gs1 and gs2), the gs1-2- double mutant, and the gs0 quadruple mutant (mutated at all four signals utilized for N-linked glycosylation in SFFVAP-L env) were made. The primary translation products (gp52) of single-site mutant envs were processed into more highly glycosylated forms, and the corresponding viruses induced splenomegaly in susceptible mice, whereas the gs1-2- and gs0 proteins were not processed, and these viruses were not pathogenic. Unprocessed env proteins of both pathogenic and nonpathogenic mutants coprecipitated with EpoR. In the BaF3 cell assay for epoR-dependent mitogenicity, the pathogenic single mutants induced factor-independent growth efficiently whereas the nonpathogenic gs1-2- and gs0 mutants did not. These data demonstrate that the ability of gp52 to form complexes with EpoR in the endoplasmic reticulum is not sufficient for either mitogenicity in cell culture or induction of splenomegaly in mice while supporting the hypothesis that pathogenicity and mitogenicity of SFFV both result from an interaction between EpoR and SFFV env protein.
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PMID:Erythropoietin receptor (EpoR)-dependent mitogenicity of spleen focus-forming virus correlates with viral pathogenicity and processing of env protein but not with formation of gp52-EpoR complexes in the endoplasmic reticulum. 843 18

The term 'erythrocytosis' has advantages over 'polycythaemia' to describe patients with a raised haematocrit (PCV) and deserves to be more widely used. Measurement of red cell mass (RCM) and its relation to that expected for an individual's height and weight permits initial subdivision of erythrocytosis into absolute (increased RCM) or apparent normal RCM. Absolute erythrocytosis may be primary (intrinsically abnormal marrow erythropoiesis) or secondary (increased erythropoietin drive in response to pathological events outside the bone marrow). Both primary and secondary erythrocytosis may be either congenital or acquired. Idiopathic erythrocytosis is a third, probably heterogenous, group within the absolute erythrocytoses. Familial abnormalities of the erythropoietin receptor underlie the primary congenital subgroup. Polycythaemia vera (PV), the clonal myeloproliferative disorder, is so far, the only primary acquired disorder. Newer diagnostic investigations such as serum erythropoietin estimation, improved karyotypic analysis, in vitro culture of erythroid colonies and estimation of spleen size before splenomegaly is palpable, have permitted some modification of the traditional diagnostic criteria of polycythaemia vera. This may allow more confident diagnosis and, together with improved testing for causes of secondary erythrocytosis, may reduce the number of patients so far unsatisfactorily consigned to the idiopathic erythrocytosis group.
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PMID:The classification and diagnostic criteria of the erythrocytoses (polycythaemias) 1079 8

The nuclear proto-oncogene c-myb plays crucial roles in the growth, survival, and differentiation of hematopoietic cells. We established three lines of erythropoietin receptor-transgenic mice and found that one of them exhibited anemia, thrombocythemia, and splenomegaly. These abnormalities were independent of the function of the transgenic erythropoietin receptor and were observed exclusively in mice harboring the transgene homozygously, suggesting transgenic disruption of a certain gene. The transgene was inserted 77 kb upstream of the c-myb gene, and c-Myb expression was markedly decreased in megakaryocyte/erythrocyte lineage-restricted progenitors (MEPs) of the homozygous mutant mice. In the bone marrows and spleens of the mutant mice, numbers of megakaryocytes were increased and numbers of erythroid progenitors were decreased. These abnormalities were reproducible in vitro in a coculture assay of MEPs with OP9 cells but eliminated by the retroviral expression of c-Myb in MEPs. The erythroid/megakaryocytic abnormalities were reconstituted in mice in vivo by transplantation of mutant mouse bone marrow cells. These results demonstrate that the transgene insertion into the c-myb gene far upstream regulatory region affects the gene expression at the stage of MEPs, leading to an imbalance between erythroid and megakaryocytic cells, and suggest that c-Myb is an essential regulator of the erythroid-megakaryocytic lineage bifurcation.
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PMID:Transgene insertion in proximity to the c-myb gene disrupts erythroid-megakaryocytic lineage bifurcation. 1694 Jan 83