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

To elucidate the contributions of GATA-1 to definitive hematopoiesis in vivo, we have examined adult mice that were rendered genetically defective in GATA-1 synthesis (Takahashi et al, J Biol Chem 272:12611, 1997). Because the GATA-1 gene is located on the X chromosome, which is randomly inactivated in every cell, heterozygous females can bear either an active wild-type or mutant (referred to as GATA-1.05) GATA-1 allele, consequently leading to variable anemic severity. These heterozygous mutant mice usually developed normally, but they began to die after 5 months. These affected animals displayed marked splenomegaly, anemia, and thrombocytopenia. Proerythroblasts and megakaryocytes massively accumulated in the spleens of the heterozygotes, and we showed that the neomycin resistance gene (which is the positive selection marker in ES cells) was expressed profusely in the abnormally abundant cells generated in the GATA-1.05 mutant females. We also observed hematopoiesis outside of the bone marrow in the affected mutant mice. These data suggest that a small number of GATA-1.05 mutant hematopoietic progenitor cells begin to proliferate vigorously during early adulthood, but because the cells are unable to terminally differentiate, this leads to progenitor proliferation in the spleen and consequently death. Thus, GATA-1 plays important in vivo roles for directing definitive hematopoietic progenitors to differentiate along both the erythroid and megakaryocytic pathways. The GATA-1 heterozygous mutant mouse shows a phenotype that is analogous to human myelodysplastic syndrome and thus may serve as a useful model for this disorder.
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PMID:Role of GATA-1 in proliferation and differentiation of definitive erythroid and megakaryocytic cells in vivo. 965 42

MMM is a chronic myeloproliferative disorder characterized by bone marrow fibrosis and neoangiogenesis, constitutive release ofa high number of CD34+ stem cells from the bone marrow, and extramedullary hematopoiesis. It presents with heterogeneous clinical features in which anemia and progression to symptomatic splenomegaly dominate. The pathogenesis is undefined, but the dual action of deregulation of the bFGF pathway may influence myeloproliferation, myelofibrosis, and neoangiogenesis. Animal models suggest that chronic exposure to high doses of thrombopoietin or impairment of the capacity of megakaryocytes to differentiate into platelets, as occurs in the GATA-1(low) mice, is a necessary event for myelofibrosis. Allogeneic stem cell transplantation offers a chance of cure, and low conditioning regimens may extend the age of transplantable patients with lower mortality. Autologus stem cell transplantation and splenectomy are risky procedures that may be considered in patients with advanced disease when conventional therapies for correcting anemia (danazol, recombinant human erythropoietin, or cyclosporine) or chemotherapy for splenomegaly and myeloproliferation (hydroxyurea or interferon alfa) have failed. Thalidomide has been tested in numerous series, and its capacity to improve anemia and thrombocytopenia while reducing splenomegaly has been documented.
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PMID:Myelofibrosis with myeloid metaplasia. 1456 Jul 83

Transcription factor GATA-1 is essential for erythroid cell differentiation. GATA-binding motifs have been found in the regulatory regions of various erythroid-specific genes, suggesting that GATA-1 contributes to gene regulation during the entire process of erythropoiesis. A GATA-1 germ-line mutation results in embryonic lethality due to defective primitive erythropoiesis and GATA-1-null embryonic stem cells fails to differentiate beyond the proerythroblast stage. Therefore, the precise roles of GATA-1 in the later stages of erythropoiesis could not be clarified. Under the control of a GATA-1 gene hematopoietic regulatory domain, a GATA-1 mutant lacking the N-finger domain (DeltaNF mutant) was over-expressed in mice. These mice exhibited abnormal morphology in peripheral red blood cells (RBCs), reticulocytosis, splenomegaly, and erythroid hyperplasia, indicating compensated hemolysis. These mice were extremely sensitive to phenylhydrazine (PHZ), an agent that induces hemolysis, and their RBCs were osmotically fragile. Importantly, the hemolytic response to PHZ was partially restored by the simultaneous expression of wild-type GATA-1 with the DeltaNF mutant, supporting our contention that DeltaNF protein competitively inhibits the function of endogenous GATA-1. These data provide the first in vivo evidence that the NF domain contributes to the gene regulation that is critical for differentiation and survival of mature RBCs in postnatal erythropoiesis.
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PMID:Transgenic over-expression of GATA-1 mutant lacking N-finger domain causes hemolytic syndrome in mouse erythroid cells. 1567 Feb 13