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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied N-ras and Ki-ras point mutations respectively at codons 12-13 and 12 in 15 patients with myelodysplastic syndromes (MDS) using the polymerase chain reaction (PCR) method for DNA amplification, and slot blot hybridization to allele specific oligonucleotide (ASO) probes. We analysed peripheral blood and bone marrow samples collected at diagnosis and repeatedly during the chronic phase of the disease to define when the activation occurred and in which haemopoietic cell populations, in order to establish possible relationships between clinical and molecular features. In three cases the N-ras oncogene was mutated at codon 12 in every cell population, both at diagnosis and throughout the chronic phase. Point mutations were not seen at the 12 codon of the Ki-ras oncogene. In patients lacking activated ras oncogene at diagnosis, mutations were not discovered during the entire period of observation. Therefore in our cases disease progression and leukaemic transformation did not correlate with the presence of the activated N-ras. Our data suggest that ras activation occurs early in the pathogenesis of MDS and involves a haemopoietic progenitor with multiple differentiative capacity, without however conferring an apparent proliferative advantage on its progeny.
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PMID:Ras activation in myelodysplastic syndromes: clinical and molecular study of the chronic phase of the disease. 218 88

The ras proto-oncogenes encode membrane bound proteins (p21) which are structurally distinct from the proteins encoded by the activated transforming ras genes. These activated ras genes have been identified in various human tumors as well as their preneoplastic lesions such as colorectal tumors (20-40%), pancreatic carcinomas (95%), lung carcinomas (20-30%), myelodysplasia (40%) and acute myeloid leukemia (30%). The activation of ras p21 is due to amino acid substitutions at positions 12, 13 or 61 of the p21 protein. This report describes two monoclonal antibodies designated D129 and D146 raised against a synthetic peptide corresponding to amino acids 5-16 of ras p21 activated by the substitution of aspartic acid for glycine at position 13. D129 and D146 react specifically with the peptide with the aspartic acid substitution at position 13, but not with the peptide with valine at position 13 or the peptide containing the normal glycine at position 13. Western blot analysis demonstrates that D129 and D146 react specifically with p21 extracted from transformed NIH3T3 fibroblast lines containing aspartic acid at position 13. These studies also demonstrate that D146 is able to detect the activated p21 with aspartic acid at position 13 that is shed into the culture media. Studies demonstrate that MAb D146 specifically immunoprecipitates the cellular p21 with aspartic acid at position 13 from transformed NIH3T3 cells, whereas D129 cannot immunoprecipitate the activated p21. Using a sandwich ELISA format, D146 is able to detect the p21 with position 13 aspartic acid from cell extracts and culture fluids. The ability of D146 to function in the ELISA format raises the possibility that this assay maybe a quick and effective way of determining the presence of activated p21 with aspartic acid at position 13 in human fluids and tissues.
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PMID:Characterization of monoclonal antibodies specific to the activated ras p21 with aspartic acid at position 13. 220 49

Mutations in the ras genes frequently are found in myeloproliferative disorders. These abnormalities have prognostic significance in the myelodysplastic syndromes, but their clinical importance in other hematopathic states remains unclear. The study of this gene in leukemic conditions is providing insights into the genetic pathways leading to leukemic progression.
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PMID:The role of ras gene mutations in myeloproliferative disorders. 227 74

Restriction fragment length polymorphisms (RFLPs) of the X-chromosome genes hypoxanthine phosphoribosyl transferase (HPRT) and phosphoglycerate kinase (PGK) were studied in 34 female patients with primary myelodysplastic syndromes (MDS). Twelve patients (35%) were heterozygous at the HPRT or PGK loci for BamHI or BglI RFLPs, respectively. In eight patients showing PGK polymorphisms, clonality was determined by X-chromosome inactivation analysis. These included patients from different morphologic subtypes: four with refractory anemia (RA), two with RA and ring sideroblasts (RARS), one patient with RA with excess of blasts (RAEB), and one with chronic myelomonocytic leukemia (CMML). A monoclonal pattern of X-chromosome inactivation was observed in seven cases. In a further case characterized by bone marrow hypoplasia, peripheral blood (PB) leukocytes were polyclonal in origin. Following low-dose cytarabine therapy, reversion to polyclonal hematopoiesis was observed in a case of RAEB indicating the presence of residual normal hematopoietic stem cells with the capacity for marrow reconstitution. The clonal relation of lymphoid and granulocyte/monocyte lineages was studied directly in two cases of CMML exhibiting somatic mutations of N-ras or Ki-ras oncogenes. By selective oligonucleotide hybridization to ras gene sequences amplified in vitro by the polymerase chain reaction, a mutated ras allele was demonstrated in PB granulocytes, monocytes, and B and T lymphocytes of both patients. We conclude that MDS arise from a multipotent hematopoietic stem cell with the potential for myeloid and lymphoid differentiation.
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PMID:Clonal analysis of myelodysplastic syndromes: evidence of multipotent stem cell origin. 256 24

Results of our study on the activation of N-ras oncogene by point mutation in human leukemia and myelodysplastic syndrome have been described in this article. Point mutation was observed mainly on the 12th, 13th and 61st amino acid codon of ras genes. Therefore, oligomers containing mutations at these codons were used as probes for dot blot analysis of DNA derived from patient's bone marrow cells or leukemia cells. Polymerase chain reaction technique was used to amplify the DNA of ras genes containing 12th, 13th and 61st codons. By this technique, sensitivity of the method to detect the point mutations in ras oncogene was remarkably increased. Detection of the mutation in ras gene is considered to be very useful for the diagnosis, determination of remission and finding of relapse at an early stage. Study on the fused gene of bcr-abl, its mRNA and protein in chronic myelogenous leukemia is a good and reliable method to prove the existence of Ph1 positive chromosome by gene technology. Identification of the Ph1 acute lymphoblastic leukemia (ALL) has become possible by studying abl oncogene in Ph1 positive ALL. This method can be used also for the diagnosis of Ph1 ALL.
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PMID:[Oncogenes in human leukemia]. 265 Jun 33

Using synthetic oligonucleotide hybridization, we have found a ras mutation in 11 of 27 patients (41%) with primary or non-therapy related myelodysplastic syndrome (MDS). This high incidence of mutation, mainly of the N-ras oncogene, was generally found in patients with disease progression to acute leukemia (8 of 11 patients = 73%). Two general mechanisms of ras mutation were found. In five patients the ras mutation was present in only a fraction of the cells; sometimes appearing in late stages of the disease, suggesting that it can occur in a differentiated cell clone. In six other patients, the ras mutation was present in the great majority of bone marrow or blood cells. The mutation was detected in mature normal lymphocytes and persisted following a complete clinical remission in two of these patients, implying that the ras mutation can occur in an early stage of cell differentiation or stem cell. Patients with a ras mutation had a median survival of nine months (all patients dead) compared to 16 patients without a ras mutation that had a median follow-up of 16 months (10 patients alive; P less than 0.005). Since 9 of the 11 patients (82%) with a ras mutation were found to have an abnormal monocytic component at diagnosis or during disease evolution, it is possible that in myeloid disorders a ras mutation is preferentially associated with myelomonocytic cell differentiation.
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PMID:Mechanisms of ras mutation in myelodysplastic syndrome. 265 75

Leukemias and lymphomas are the most extensively characterized forms of neoplasia at the molecular genetic level. Southern blot assays to detect rearrangement of antigen-receptor genes have proven useful in the diagnosis of monoclonality in B- and T-cell neoplasms. This type of assay has clinical utility in that it can detect a small monoclonal population and provide unique information about the clone. Characteristic chromosomal translocations found in various histological types of leukemia and lymphoma can also be detected by Southern blot or by polymerase chain-reaction-based techniques. Detection of point mutations in the ras family of oncogenes may have prognostic importance and permit detection of a monoclonal population in myelodysplastic syndromes and acute leukemias. Viruses may also be involved with leukemia and lymphoma. As assays involving molecular genetics became increasingly important in the evaluation of these neoplasms, greater efforts are needed to improve their technical, laboratory, and clinical aspects.
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PMID:Molecular genetics of leukemia and lymphoma. 266 34

We have screened a large series of primary human leukemias for activating point mutations at codons 12, 13 and 61 of the N-ras and K-ras proto-oncogenes and at codons 12 and 61 of the H-ras proto-oncogene by using panels of oligonucleotide probes in conjunction with polymerase chain reaction gene amplification. 13 of 64 (20%) acute lymphoblastic leukemia cases had ras gene mutations mostly involving N-ras codon 12/13, G-A (gly-asp) transitions. Consistent with previous studies, a comparable pattern and frequency of ras mutation was found amongst 45 cases of acute myeloid leukemia and myelodysplasia. By contrast, of 30 cases of mature B cell chronic lymphocytic leukemia, only one in terminal prolymphocytoid transformation harboured an activated ras gene. These patterns of mutation did not correlate with ras gene methylation state, a finding not obviously compatible with differential gene accessibility being an important determinant of ras gene mutation patterns in leukemogenesis. Our data suggest that activated ras is more important in tumourigenesis of immature than mature lymphocyte progenitors whilst similar mechanisms associated with aetiology and/or target cell susceptibility probably underlie the similar patterns of ras gene mutations seen in acute leukemias of both myeloid and lymphoid cell lineages.
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PMID:Analysis of ras gene mutations and methylation state in human leukemias. 266 44

The conversion of normal haemopoietic stem cells to myelodysplastic and then to leukaemic cells is marked by a number of events leading to progressive genetic changes in the abnormal clonal population. Cytogenetic evidence points to abnormalities at specific chromosomal locations, commonly involving chromosomes 5 and 7, where there are a particular concentration of genes directly involved in the regulation of haemopoietic proliferation and differentiation. These include GM-CSF, IL-3, M-CSF, erythropoietin and others. Other genes that may be involved in the preleukaemic process are so-called 'oncogenes' such as met on chromosome 7q and fms on 5q (which codes for the M-CSF receptor) that may be deleted or translocated. The ras gene family is activated by point mutations in a wide variety of malignant states, including myelodysplasia and acute myeloblastic leukaemia. At the present time we do not know the cause of these genetic lesions, their functional significance or the sequence in which they occur.
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PMID:Oncogenes in the myelodysplastic syndrome. 267 42

The clinical association of an increased incidence of acute myelogenous leukemia (AML) with previous chemoradiotherapy, the detection of specific karyotypic changes in these secondary (therapy-induced) cases of AML and the discovery of increasing levels of oncogene-specific RNA in leukemia cells suggest that one potential site of action of environmental agents might be the proto-oncogenes in human hematopoietic stem cells. The location of human proto-oncogenes at the sites of chromosome breaks and/or translocations in cells from some patients with leukemia or lymphoma is a striking observation. These data stimulated research into the mechanism of activation of specific oncogenes that change the biology of human hematopoietic cells. Recent investigations have focused upon several areas that might alter cell biology including: 1) translocation and/or inversion of chromosome fragments containing a proto-oncogene to a location where other gene sequences can stimulate oncogene activation, 2) replication of copy number of proto-oncogenes or increased transcriptional activity and 3) point mutation in proto-oncogenes leading to a structurally altered protein. The third area of research has recently received significant attention with respect to the potential role of three ras genes (c-Harvey-ras, c-Kirsten-ras and N-ras) in human leukemias and myelodysplastic syndromes. Recent studies have proposed a model for leukemogenic transformation of human hematopoietic cells by the product of a mutated ras oncogene. Mutations at codons 12, 13 or 61 of the first exon of its 4.7 Kb of DNA (for c-Ha-ras) have been described. Other data revealing an absence of such mutations in the ras genes of many human leukemias and the absence of detectable transcription of ras genes in many alkylating agent-associated cases of AML, suggest that while ras mutations may be involved in some settings, there are probably multiple genetic pathways to leukemogenic transformation of human hematopoietic cells.
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PMID:ras mutations in human leukemia and related disorders. 268 41


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