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)

Patients with a myelodysplastic syndrome (MDS) which has a risk of leukaemic change exhibit a variable clinical course. It has been suggested that the development of leukaemia in patients with MDS may be related to chromosomal abnormalities or genetic alterations: somatic mutation of the N-ras gene is now considered to be a critical step in the genetic basis of human leukaemogenesis. Here we report that DNAs of bone-marrow cells from three out of eight patients with MDS contained an activated N-ras oncogene, as detected by an in vivo selection assay in nude mice with transfected NIH 3T3 cells. Molecular analysis revealed the same single nucleotide substitution at codon 13 in all three transforming N-ras genes. Each of the three patients showed a progression of the disease and a resulting leukaemic change within the following year. Our observation of the mutation at codon 13 in leukaemic cell DNAs from all three cases suggests that activation of the N-ras gene is important in the development of leukaemia in some MDS cases.
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PMID:A point mutation at codon 13 of the N-ras oncogene in myelodysplastic syndrome. 329 62

Previous work has established the presence of an unbalanced chromosome abnormality [+der(1),t(1;7)(p11;p11)] in some therapy-associated myelodysplastic disorders. Recently the EGF receptor has been found to reside at 7p11. Using a probe specific for erb B oncogene, which encodes a truncated form of the EGF receptor, we examined RNA and DNA derived from bone marrow and peripheral blood mononuclear cells from three patients with myelodysplastic syndromes (MDS) and one with acute lymphocytic leukemia (ALL), all bearing an abnormal clone in their bone marrow with a similar unbalanced 1;7 translocation. DNA-excess slot blot hybridization to 5'-32p-labeled cellular RNA revealed from ten- to thirtyfold enhancement in accumulation of mRNA specific for erb B in both peripheral blood and bone marrow cells of the three MDS patients when compared to normal controls. In addition, enhancement of H-ras mRNA accumulation was detected in some, though expression of other genes such as actin, N-ras, myc, src, B-lym, and 20 other genes was not found to be enhanced. Increased erb B expression was not apparent in mononuclear cells from patients with other hematologic disorders such as chronic lymphocytic leukemia, Hodgkin's disease, or lymphoma. Southern blot analysis of restriction-enzyme-cleaved DNA from three MDS patients with an unbalanced 1;7 translocation revealed that erb B gene was amplified at least twentyfold in peripheral blood white blood cells, while levels of actin hybridization were comparable to those of the controls. No such amplification was evident in the ALL patient. Our data suggest that +der(1),t(1;7)(p11;p11) chromosomal anomalies can be specifically associated with amplification of erb B DNA and RNA sequences.
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PMID:Amplification of RNA and DNA specific for erb B in unbalanced 1;7 chromosomal translocation associated with myelodysplastic syndrome. 346 13

The synthetic oligonucleotide probes were used for the analysis of N-ras oncogenes detected in human acute leukemias. The mutations of N-ras genes were observed to occur randomly among the subtypes of myeloid leukemias, whereas the N-ras mutations at codon 12 are more likely to occur in lymphoid leukemias than other mutations. The mutations at codon 13 of the N-ras gene were not detected in acute leukemias although they were found in myelodysplastic syndrome that is considered to be a preleukemic state.
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PMID:Activation mechanism of the N-ras oncogene in human leukemias detected by synthetic oligonucleotide probes. 347 29

The presence of a transforming gene in the DNA of bone marrow cells from patients with myelodysplastic syndrome (MDS) was studied using an in vivo selection assay in which NIH 3T3 cells transfected with human DNA were injected into nude mice in order to observe the growth of the tumor. The transforming gene was present in 12 out of 18 cases. The Alu sequence was demonstrated in the tumor grown after injection of transfected NIH 3T3 cells from 10 patients. Among these 10 Alu sequences, the human N-ras oncogene was present in 3 cases. Analysis of nucleotide sequences of the exons of human N-ras oncogenes cloned from the tumors revealed a single point mutation of the codon encoding the 13th amino acid of exon 1 from guanine to cytosine in all 3 cases of MDS. A one-year follow-up study of these MDS cases showed that in the patients positive for the transforming gene, the disease state progressed from PARA, PASA to RAEB or from RAEB to acute leukemia in 6 out of 7 cases, while in the 6 negative patients, no change was observed in their disease states. It was considered that the mutation of the N-ras gene at the 13th amino acid codon of exon 1 was fairly specific to MDS and that presence of the transforming gene may be used for predicting the progress of the disease.
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PMID:[Transforming gene in the preleukemic state]. 360 44

Activation of the N- and K-ras proto-oncogenes is the most common molecular abnormality in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In retrospective studies, approximately 3-36% of MDS patients were reported to harbor a mutated ras proto-oncogene, with some series suggesting the presence of ras-mutations are associated with progressive disease and a poor prognosis. Since hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) are currently used for therapy in MDS but may stimulate the proliferation of leukemic cells, we assessed the frequency and significance of ras mutations in 27 MDS patients, 15 of whom underwent G-CSF therapy. Patients were analyzed for the presence of mutations in codons 12, 13, and 61 of the N- and K-ras proto-oncogenes. Only three patients (11%, two refractory anemia with excess of blasts (RAEB), one RAEB in transformation (RAEB-T)) harbored activated ras oncogenes with the mutations localized in N-ras codons 12 and 61. Patients were followed for periods of up to 4 years or until death supervened. Patients exhibiting ras mutations were no more likely to develop AML compared to ras-negative patients (1/3 vs. 10/24) or to have decreased survival (p = 0.64). These data indicate that, in this group of MDS patients, ras mutations do not appear to correlate with a poor prognosis, and do not adversely interact with exogenously administered G-CSF.
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PMID:Mutations in the ras proto-oncogenes in patients with myelodysplastic syndromes. 751 75

The clinical and biological characteristics of myelodysplastic syndrome (MDS) in acute leukemic transformation were studied in 23 patients. All had myeloid transformation according to FAB criteria, but coexpression of lymphoid-associated antigens was detected in five of the 20 patients who underwent an immunophenotypic study. Rearrangement of the immunoglobulin heavy chain gene was also observed in one of the five patients who coexpressed lymphoid markers and that of the T-cell receptor beta chain gene in another one. None had pure lymphoid transformation. Clonal chromosomal abnormalities were noted in 12 (63%) of the 19 patients who underwent cytogenetic study, most commonly - 7 (six patients or 32%). In the 18 patients who underwent serial analyses both at MDS diagnosis and at acute transformation, seven (39%) underwent karyotypic evolution. The most common new or additional aberrations were +8 and +21. N-ras gene mutation was detected in two of the nine patients at acute leukemic transformation. The median interval from diagnosis of MDS to onset of acute transformation was 10 months (1-36 months). Patients with a normal karyotype at diagnosis had a significantly longer chronic phase duration than those with chromosomal abnormalities (median of 20 months vs. 5 months). However, all had a short survival time after diagnosis of acute leukemia, whether chromosomal anomalies were present or not.
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PMID:Acute leukemic transformation of myelodysplastic syndrome--immunophenotypic, genotypic, and cytogenetic studies. 756 69

Myelodysplastic syndromes (MDS) are increasingly recognized as a cause of bone marrow failure, and are at least as frequent as acute myeloid leukemias. While the overall incidence is about 2-4/100,000/year, incidence figures rise steeply with age. Incidence rates of 20-30/100,000/year in persons over 70 demonstrate that MDS are among the most common hematological neoplasias in this age group. However, due to difficulties of diagnosis and classification, patient registration in population-based registers is far from complete. As a prerequisite for truly representative statistics, future revisions of disease classification systems must incorporate MDS as a separate group of disorders. The difficulties in conducting epidemiological studies also impede the identification of risk factors for the development of MDS. Current knowledge of occupational risk factors is also reviewed here. More rapid progress in our understanding of MDS may come from recent advances in methodology that have begun to shed some light on the cytogenetic and molecular aspects of leukemogenesis in general, and MDS in particular. Non-random chromosomal changes can be found in about 50% of cases at diagnosis, but they are probably late events in the evolution of MDS, reflecting the progressive genomic instability of the premalignant clone. Proto-oncogene mutations have also been suggested to be relevant to the pathogenesis of MDS, but longitudinal studies of point mutations of the N-ras proto-oncogene revealed that such events, although often associated with rapid deterioration and transformation to AML, also appear to be late events during the course of disease. Therefore, it remains a major challenge to identify those lesions that initiate the multistep development of preleukemia. As the incidence of MDS correlates strongly with age, it is reasonable to presume that age-dependent changes of the hematopoietic system may play a role in the initiation of MDS. Aging is probably associated with a compromised marrow reserve through reduction in the size of the stem cell pool. Through increased proliferative activity, the remaining stem cells may be particularly vulnerable to mutagenic insults. Immunological attack on stem cells, mitochondrial DNA mutations, and the regulatory influence of the hematopoietic microenvironment must also be considered as possibly contributing to the early stages of MDS.
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PMID:Epidemiological and etiological aspects of myelodysplastic syndromes. 771 33

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

Oncogene mutations are frequently found in several tumour types and, among these, point mutations of the ras gene are particularly significant. A predominance of N-ras mutations has been found in the bone marrow DNA of patients with myelodysplastic syndrome (MDS) or acute myelogenous leukaemia (AML). On the other hand, increased levels of plasma DNA have previously been observed in patients suffering from various malignant diseases. In the present work we have investigated, by polymerase chain reaction (PCR), point mutations of the N-ras gene in the DNA of plasma, blood cells and bone marrow of 10 patients suffering from AML or MDS. The different ras mutations detected in five cases were always present in the plasma DNA while sometimes absent in the DNA of peripheral blood cells or bone marrow. This indicates that a bone marrow biopsy or aspiration does not necessarily contain all the malignant clones involved in the disease. Plasma could thus prove to be an easily accessible and useful material for detection and monitoring of myeloid disorders.
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PMID:Point mutations of the N-ras gene in the blood plasma DNA of patients with myelodysplastic syndrome or acute myelogenous leukaemia. 791 71

Minute alterations of the p53 tumor suppressor gene and N-ras oncogene were investigated in 106 samples for the p53 gene and 23 samples for the N-ras gene obtained from patients with various types of hematologic malignancies using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct nucleotide sequencing. Mobility shifts suggesting sequence alteration were observed in 9 cases (8.5%) in exons 5 through 8 containing evolutionarily highly conserved regions of the p53 gene by PCR-SSCP; missense point mutations in 3 cases (1 acute myelogenous leukemia (AML), 1 chronic myelogenous leukemia (CML) in the accelerated phase, and 1 CML in the blast crisis), silent point mutation in 1 case (malignant lymphoma), and frame shift mutations due to insertions and deletions causing stop codons in 3 cases (1 AML, 1 CML in the chronic phase and 1 acute lymphoblastic leukemia (ALL)). p53 gene alterations did not always cluster within evolutionarily highly conserved regions, and there were various base change forms in cases with p53 point mutations. p53 mutations were detected in 2 cases out of 4 cases with 17 monosomy. There was no case with p53 gene alteration in myelodysplastic syndrome (MDS) cases. Mobility shifts suggesting sequence alteration were observed in 5 cases (22%) in exon 1 and 2 of the N-ras gene by PCR-SSCP. 3 cases (1 MDS, 1 MDS overt AML and 1 ALL) were detected to contain missense point mutations. However, simultaneous mutations in both the genes were detected in only 2 cases out of 23, thereby indicating infrequent occurrence of concomitant mutation of both the genes in hematologic malignancies. Alterations of the p53 and the N-ras genes are involved in the tumorigenesis, progression and prognosis of at least some cases of hematologic malignancies, in spite that they are relatively infrequent.
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PMID:[Molecular study on minute alterations of the p53 and the N-ras genes in hematologic malignancies]. 792 79


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