Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The presence of activated transforming genes was investigated in four patients with therapy-related leukemia and in three with therapy-related myelodysplastic syndrome. DNA of bone marrow cells from six of the patients exhibited transforming activity in the tumorigenicity assay. Five of the six patients who were positive in the tumorigenicity assay contained activated N-ras oncogenes, and three contained activated K-ras oncogenes. Thus, concurrent activation of N-ras and K-ras oncogenes was observed in two patients. In vitro DNA amplification followed by oligonucleotide dot-blot analysis was used to investigate mutations in codons 12, 13, and 61 of the N-ras and K-ras oncogenes. Two patients exhibited an N-ras mutation, substituting aspartic acid (GAT) for glycine (GGT), and three patients exhibited an N-ras codon 13 mutation, substituting valine (GTT) for glycine. Two patients exhibited K-ras codon 12 mutations, substituting aspartic acid (GAT) or cysteine (TGT) for glycine (GGT), respectively, and one case exhibited a K-ras codon 61 mutation, substituting lysine (AAA) for glutamic acid (CAA). Cytogenetic analysis revealed that loss of chromosome 7 was frequent (four patients: 57%). Our data indicate that activation of N-ras and K-ras genes, as well as loss of heterozygosity for specific alleles on chromosome 7, plays a more important role in the leukemogenesis of both therapy-related leukemia and myelodysplastic syndrome.
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PMID:Transforming genes and chromosome aberrations in therapy-related leukemia and myelodysplastic syndrome. 185 83

Mutations in codons 12 or 13 of the first exon of the N-RAS gene have been reported in myelodysplastic syndromes (MDS) in frequencies that vary between 9% and 40% depending on the techniques used in analysis. Gene amplification and direct sequencing provides the only unambiguous method of detecting those mutations that induce amino acid alterations. Using this technique, we analyzed 21 MDS patients for mutations in exon-1 of N-RAS. Codon 12 mutations substituting aspartic acid (GAT) for glycine (GGT) were found in four cases, and a codon 13 mutation substituting alanine (GCT) for glycine (GGT) was detected in one patient. We conclude that N-RAS exon-1 mutations in one patient. We conclude that N-RAS exon-1 mutations producing amino acid changes occur in about 20% to 25% of MDS cases.
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PMID:Analysis of N-RAS exon-1 mutations in myelodysplastic syndromes by polymerase chain reaction and direct sequencing. 264 13

Activation of the cellular oncogene c-N-ras has been frequently observed in DNA from leukemic cells in acute myeloid leukemia (AML). Ras gene activation sufficient to mediate in vitro transformation and rodent tumorigenesis usually results from point mutations and amino acid substitutions in the 12th or 61st codons. In AML and the related myelodysplastic syndromes, amino acid substitution at the 13th codon has been observed. An activated c-N-ras gene from a 45-year-old patient with AML was isolated by transfection analysis and subjected to molecular cloning and sequence analysis. A point mutation of the 12th codon (GGT to GAT) resulting in aspartic acid substitution for glycine was observed. In other neoplasms such as colon cancer, specific ras mutations occur predominantly (e.g., K-ras, codon 12). This predominance has been of demonstrable value in analyzing large cohorts for ras activation with techniques that are rapid and economical, such as oligonucleotide hybridization. It had previously been thought that such a predominance for activation of c-N-ras at codon 13 existed in AML; however, this study in concert with others underscores the importance of 12th codon c-N-ras mutations, along with 13th and 61st codon mutations in the molecular pathogenesis of AML. Guanylate to adenylate transition mutations are commonly observed in AML and may provide insight into potential environmental leukemogens. Addressing all commonly prevalent ras activating mutations bears impact in the future design of molecular surveys of the role of ras activation in leukemogenesis.
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PMID:12th codon mutation resulting in c-N-ras activation in acute myelogenous leukemia. 327 72

Nine cases of overt acute nonlymphocytic leukemia and four cases of preleukemia or a myelodysplastic syndrome, all related to intensive treatment with alkylating agents, were studied cytogenetically and investigated using a rapid and sensitive dot blot screening procedure for point mutations in the Ha-ras, Ki-ras, and N-ras protooncogenes within codons 12, 13, and 61. The technique involves a selective amplification of genomic DNA sequences containing the codon sequence of interest, in combination with oligonucleotide hybridization. Examining fractionated mononuclear cells from bone marrow or peripheral blood, an N-ras mutation at position 13 was observed in one patient with overt leukemia, resulting in a base change from GGT to TGT thus converting glycine to cysteine. The other cases exhibited no ras gene mutations. It is surprising that c-ras mutations are only occasionally observed in overt acute nonlymphocytic leukemia related to treatment with alkylating agents, as such abnormalities have often been observed in acute nonlymphocytic leukemia de novo, and as many alkylating agents are known to produce DNA adducts leading to point mutations and substitution of single amino acids. The fact that deletions of varying parts of the long arms of chromosomes 5 and 7 are observed in most cases of therapy-related acute nonlymphocytic leukemia and preleukemia, as confirmed by our own series of 71 patients, suggests that loss of heterozygosity for specific alleles on the two chromosomes, rather than activation of a protooncogene, could be an important step in leukemogenesis.
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PMID:Point mutation of the ras protooncogenes and chromosome aberrations in acute nonlymphocytic leukemia and preleukemia related to therapy with alkylating agents. 328 Jan 21

Karyotypic analysis was performed in a total of 69 patients with well-characterized idiopathic myelofibrosis. Karyotypic abnormalities were detected in 46% of cases examined during the chronic phase (29/63); with three abnormalities, del(13q), del(20q) and partial trisomy 1q, accounting for 75% of all abnormalities at diagnosis. The absence of del(5q), trisomy 8 and 21, as well as the rarity of monosomy 7, contrasts with pooled published data and may reflect our exclusion of closely related disorders, in particular MDS with fibrosis. Chromosomal aberrations increased to approximately 90% (8/9) in patients analysed during acute transformation. Mutational activation of codons 12, 13 and 61 of N-, Ha- and Ki-ras genes were assessed by polymerase chain reaction and hybridization with synthetic non-radioactive digoxigenin-labelled probes. Three mutations were detected in samples of peripheral blood DNA taken from 50 patients during the chronic phase of their disease: one N12 Asp (GGT-->GAT) and two N12 Ser (GGT-->AGT) mutations. The results from this study indicate that karyotypic abnormalities are present in at least 29% of cases at diagnosis and that del(13q), del(20q) and partial trisomy 1q are the most frequent findings. Ras mutations were relatively infrequent (6%) and appeared restricted to the N-ras gene. Karyotypic analysis at diagnosis was found to be of prognostic significance.
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PMID:Karyotypic and ras gene mutational analysis in idiopathic myelofibrosis. 781 70

Long-term survivors of aplastic anemia (AA) have a high incidence of clonal disorders, in particular paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndromes (MDS), and acute nonlymphocytic leukemia. To investigate the potential involvement of N-RAS gene mutations in the predisposition to leukemic evolution, a subset of patients at potentially increased risk for clonal disease was selected based on evidence of existing clonal evolution. Nine patients showed a monoclonal pattern of X-chromosome inactivation, 18 demonstrated a PNH clone, and in 3 MDS developed during the course of this study. No mutations were detected during the aplastic phase of disease; 2 of 3 patients with MDS after AA also showed no mutations. However, in 1 patient in whom the disease transformed from AA/PNH to MDS, a mutation of GGT --> GAT at N-RAS codon 13 became detectable, whereas the PNH mutation disappeared. The authors conclude that N-RAS mutations are not an early event preceding transformation of AA or AA/PNH to leukemia. In a subset of patients, RAS mutations may occur at the time of evolution to MDS, but preexisting RAS mutations do not explain the propensity of AA to leukemogenesis. Although PNH is also associated with leukemia, this may arise in the non-PNH cells, indicating that PIG-A gene mutation is not per se oncogenic. (Blood. 2000;95:646-650)
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PMID:N-RAS gene mutation in patients with aplastic anemia and aplastic anemia/ paroxysmal nocturnal hemoglobinuria during evolution to clonal disease. 1062 75