Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our recent establishment of several permanent in-vitro cell lines from Brown Norway rat leukemia (BNML) and the development of a clonogenic assay prompted us to undertake detailed studies on the growth control mechanism of a cell type which for several years has served as an animal model for human AML and preclinical studies. So far, these cells have no defined biological regulators but require intricate cellular interactions to sustain their growth. The effects on cell growth and clonogenicity, of agents known to modify the intracellular levels of cyclic nucleotides, were analysed. Here we report that CT binding strongly inhibited cell growth at a wide range of concentrations (10(-6)-10(-14) M) while beta chain pentameric subunits or alpha chain had no effects. Cell growth was inhibited in a dose-dependent manner. The ligand-receptor interactions mediated the alpha chain's transit through the membrane; the adenylate cyclase activation and the rise in c-AMP levels (60 min) resulted in DNA synthesis arrest (5 h), then finally ended in cell death (24-48 h). A significant decrease in the clonal ability of treated cultures was seen. A decrease of up to five logs in the clonogenic cell number was observed after 48 h of toxin treatment (10(-7) M). The growth inhibition of CT were reproduced by several agents (PGE, theophylline, isobutylmethylxanthine) known to raise intracellular c-AMP levels. Data are commented from a biochemical approach to intracellular events controlling the cell growth of this leukemia. The potential interests of c-AMP inducing agents on the eradication of this leukemia by ex-vivo marrow treatments are also considered.
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PMID:On growth regulation of the rat promyelocytic leukemia (BNML): growth inhibition and eradication of clonogenic cells by cholera toxin. 243 59

One of the major problems in the treatment of leukemia with BMT remains leukemia relapse. It has generally been established that allogeneic BMT, compared with autologous BMT, gives rise to a graft-versus-leukemia reaction (GVLR), usually associated with GVHD. To explore a possible role for post-BMT immunotherapy, recombinant human IL-2 therapy has been studied in the Brown Norway acute myelocytic leukemia (BNML), a rat leukemia model relevant for human AML. The antileukemic efficacy of rhIL-2 therapy is studied applying different doses of rhIL-2 after syngeneic or allogeneic BMT. rhIL-2 treatment post-syngeneic BMT showed a small, borderline significant GVLR. Repeated rhIL-2 treatment after allogeneic BMT resulted either in no significant antileukemic effect or in lethal GVHD when 'low' or 'high' doses were administered, respectively. An intermediate dose, however, induced a significant GVLR without the induction of (lethal) GVHD. Transplantation of allogeneic rat BM, which contains only a few lymphocytes, does not result in a significant GVLR or GVHD and thus resembles human HLA-matched allogeneic T cell-depleted (TCD) BMT. In conclusion, from the rat studies presented it appears that the GVLR lost by TCD of the allogeneic graft, may be more than fully compensated by IL-2 treatment post-allogeneic TCD BMT.
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PMID:Interleukin-2 therapy after allogeneic bone marrow transplantation for acute myelocytic leukemia: studies in a relevant rat model for AML. 771 75

Targeting of signal transduction pathways and transcriptional regulation represents an attractive approach for less toxic anti-leukaemic therapy. We combined protein kinase A (PKA) activation with a pan-peroxisome proliferator-activated receptor (PPAR) activator tetradecylthioacetic acid, resulting in synergistic decrease in viability of AML cell lines. PKA isoform II activation appeared to be involved in inhibition of proliferation but not induction of apoptosis in HL-60 cells. Inhibition of CREB function protected against this anti-leukaemic effect with higher efficiency than enforced Bcl-2 expression. Preclinical studies employing the rat AML model Brown Norwegian Myeloid Leukaemia also indicated anti-leukaemic activity of the combination therapy in vivo. In conclusion, combined PKA and pan-PPAR activation should be explored further to determine its therapeutic potential.
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PMID:Protein kinase A activators and the pan-PPAR agonist tetradecylthioacetic acid elicit synergistic anti-leukaemic effects in AML through CREB. 1978 2

DNMT3A codes for a DNA methyl transferase enzyme that plays a central role embryogenesis. Somatic mutations in this gene have been associated with tumorigenesis and are associated with a number of cancers. The recently described Tatton-Brown-Rahman syndrome (TBRS) is due to heterozygous germline mutations in the DNMT3A gene. So far, only one case of hematological malignancy associated with TBRS have been reported. Here, we describe the first case presenting with TBRS and medulloblastoma. We also discuss the associations between mutations in DNMT3A found in TBRS, AML, and medulloblastoma.
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PMID:The first case report of medulloblastoma associated with Tatton-Brown-Rahman syndrome. 3106 80

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.
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PMID:Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging. 3116 Mar 75