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)

RAG-1 and RAG-2 are developmentally regulated genes that are essential for the assembly of antigen receptors in lymphoid cells. Here we describe transgenic mice that carry RAG-1 and RAG-2 under the control of the proximal lck promoter. Persistent expression of RAG-1 and RAG-2 was associated with incomplete thymopoiesis and profoundly compromised cellular immunity. In addition, RAG transgenic mice rapidly developed lymphadenopathy, splenomegaly, and lymphocytic perivascular infiltrates. These effects required both RAG-1 and RAG-2, since mice that carried either gene exclusively were indistinguishable from wild-type controls. We propose that in addition to a previously documented role in V(D)J recombination, RAG-1 and RAG-2 expression must be properly regulated for completion of normal T cell development
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PMID:A regulatory role for recombinase activating genes, RAG-1 and RAG-2, in T cell development. 753 1

Fas is a member of the TNF receptor family. Binding of Fas ligand to Fas induces apoptosis in Fas-bearing cells. Fas is expressed in various cells, including thymocytes, peripheral T cells, and activated B cells. The mouse lpr mutation is a loss of function mutation of Fas. MRL-lpr/lpr mice develop lymphadenopathy and splenomegaly, and produce multiple autoantibodies, which results in autoimmune disease. In this report, we describe the establishment of a line of Fas transgenic MRL-lpr mice in which mouse Fas cDNA was expressed using the T cell-specific murine lck promoter. The transgenic mice expressed functional Fas in thymocytes and peripheral T cells, but not in B cells. The transgenic mice did not accumulate abnormal T cells (Thy-1+ B220+), but still accumulated B cells (Thy-1- B220+); they produced a large quantity of Igs (IgG1 and IgG2a), including anti-DNA Abs, and developed glomerulonephritis. These results suggest that autoreactive or activated B cells must be killed through Fas expressed in the B cells by the Fas ligand expressed in activated T cells.
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PMID:Transgenic expression of Fas in T cells blocks lymphoproliferation but not autoimmune disease in MRL-lpr mice. 955 84

Fas is a death receptor that belongs to the tumor necrosis factor receptor family and is expressed in various cell types, in particular, in lymphoid cells. A loss-of-function mutation in the Fas gene (lpr mutation) causes lymphadenopathy and splenomegaly, and accelerates autoimmune diseases in some strains of mice such as MRL. In this report, Fas cDNA driven by murine lck distal promoter was used to establish transgenic MRL-lpr mouse lines. The transgenic mice expressed functional Fas in mature T cells and B cells. The lymphadenopathy and splenomegaly caused by accumulation of abnormal T cells in the lpr mice were rescued in the transgenic mice. The number of B cells in the periphery as well as the serum IgG level were significantly reduced, and the autoimmune symptoms and mortality were ameliorated. These results indicate that both mature B cells and T cells must undergo Fas-mediated apoptosis to prevent the development of autoimmune diseases.
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PMID:Requirement of Fas expression in B cells for tolerance induction. 1178 13

TET2 is mutated/deleted with high frequencies in multiple forms of myeloid malignancies including MDS, CMML, MPN, and AML. However, little is known regarding the biological function of TET2 and its role in the pathogenesis of myeloid malignancies. To study the function of TET2 in vivo, we generated a Tet2 knock out mouse model. Deletion of Tet2 in mice led to dramatic reduction in the 5-hydroxymethylcytosine levels and concomitant increase in the 5-methylcytosine levels in the genomic DNA of BM cells. The Tet2(-/-) mice contained an increased Lin(-)Sca-1(+)c-Kit(+) (LSK) cell pool before the development of myeloid malignancies. A competitive reconstitution assay revealed that Tet2(-/-) LSK cells had an increased hematopoietic repopulating capacity with an altered cell differentiation skewing toward monocytic/granulocytic lineages. Approximately 1/3 of Tet2(-/-) and 8% of Tet2(+/-) mice died within 1 year of age because of the development of myeloid malignancies resembling characteristics of CMML, MPD-like myeloid leukemia, and MDS. Furthermore, transplantation of Tet2(-/-), but not wild-type (WT) or Tet2(+/-) BM cells, led to increased WBC counts, monocytosis, and splenomegaly in WT recipient mice. These data indicate that Tet2-deficient mice recapitulate patients with myeloid malignancies, implying that Tet2 functions as a tumor suppressor to maintain hematopoietic cell homeostasis.
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PMID:Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. 2203 42