Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We report on investigations aimed at detecting mutated RAS genes in a variety of preleukemic disorders and leukemias of myeloid origin. DNA transfection analyses (tumorigenicity assay) and hybridization to mutation-specific oligonucleotide probes established NRAS mutations in codon 12 or 61 of 4/9 acute myelocytic leukemias (AML) and three AML lines. Leukemic cells of another AML patient showed HRAS gene activation. By using a rapid and sensitive dot-blot screening procedure based on the combination of in vitro amplification of RAS-specific sequences and oligonucleotide hybridization we additionally screened 15 myelodysplastic syndromes, 26 Philadelphia chromosome-positive chronic myelocytic leukemias in chronic or acute phase, and 19 other chronic myeloproliferative disorders. A mutation within NRAS codon 12 could thus be demonstrated in a patient with idiopathic myelofibrosis and in another with chronic myelomonocytic leukemia. Moreover, mutated NRAS sequences were detected in lymphocytes, in granulocytes, as well as in monocytes/macrophages of the latter case.
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PMID:RAS gene mutations in acute and chronic myelocytic leukemias, chronic myeloproliferative disorders, and myelodysplastic syndromes. 312 17

Members of the RAS gene family have been implicated in many neoplasms with activating mutations around amino acid positions 12 and 61. We have assessed the mutational activation of H, K, and NRAS in myelodysplasia (MDS) by polymerase chain reaction and hybridization with synthetic oligonucleotide probes. Using this method, point mutations in codons 12/13 and 61 of these RAS genes were detected in 20 of 50 patients including two with refractory anemia with ringed sideroblasts (RARS). Ten normal individuals had no detectable RAS mutations. In 11 instances, DNA from patients with detectable RAS mutations were shown to register in either NIH3T3 focus-forming or nude mouse tumorigenicity assays. In addition, one patient (RARS) was shown to have an activated NRAS gene detected by a tumorigenicity assay and Southern blot analyses. Two MDS patients had mutations detected in two different RAS genes. DNA from one of these patients was observed to give rise to transformants with activated N and HRAS. Two patients with detectable NRAS mutations in the MDS stage progressed to AML and DNA from the AML stage registered positively in a transformation assay with NRAS activation. These results show that RAS mutations can occur at early, as well as late, stages of leukemic progression. The incidence of RAS mutations appears to be significantly higher in CMML than in the other subgroups (p = 0.02).
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PMID:RAS mutations in myelodysplasia detected by amplification, oligonucleotide hybridization, and transformation. 316 76

Macrocytosis in the elderly is often caused by abnormalities of haematological stem cell differentiation. In this study, a group of elderly patients was analysed for four molecular and cell biological parameters. The aim of the study was to screen elderly patients with idiopathic macrocytic anaemia or MDS for a set of alterations which are related to haematological dysplasia. The analyses used were: DNA-methylation at the calcitonin A gene 5'-area, NRAS point mutations at codons 12 and 13, in vitro colony formation of peripheral blood progenitor cells and cytogenetics of bone marrow cells. The results show that a significant portion of elderly patients with idiopathic macrocytosis have one or more of the abnormalities analysed. Hypermethylation of the calcitonin A gene 5'-area at the chromosome 11 band p15 is relatively common (7/15). Chromosomal aberrations (3/12) and NRAS oncogene point mutations (0/15) were rare findings. In vitro culture of erythroid progenitor cells was relatively frequently abnormal (7/15). Eight of our nine macrocytic patients who did not fulfill the FAB criteria for MDS had at least one of the alterations studied; this suggests that these patients might represent early phases of a stem cell disorder.
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PMID:Idiopathic macrocytic anaemia in the aged: molecular and cytogenetic findings. 766 57

Children with neurofibromatosis, type 1 (NF-1) are at increased risk of developing malignant myeloid disorders and their bone marrows frequently show loss of the normal allele of the NF1 tumor-suppressor gene. NF1 encodes a protein called neurofibromin, which accelerates guanosine triphosphate (GTP) hydrolysis on the p21ras (Ras) family of signaling proteins. We used a genetic approach to test the hypothesis that NF1 negatively regulates myeloid cell growth through its effect on Ras. This model predicts that, if RAS mutations and loss of NF1 function deregulate myeloid growth by the same biomechanical mechanism, then activating RAS mutations will be restricted to children with malignant myeloid disorders who do not have NF-1. We studied 71 children, including 28 with bone marrow monosomy 7 syndrome (Mo7), 35with juvenile chronic myelogenous leukemia (JCML), three with other forms of preleukemia, and five with acute myelogenous leukemia (AML), for activating mutations of KRAS and NRAS. The incidence of RAS mutations was 21% (12 of 55) in patients without NF-1 and 0% (zero of 16) in children with NF-1 (P = .04). Among the 55 patients who did not have NF-1, we found RAS mutations in four of 27 with Mo 7, in five of 24 with JCML, in two of 3 with AML, and in a patient with myeloproliferative syndrome (MPS). These data from primary human cancer cells provide strong genetic evidence that NF1 limits the growth of myeloid cells by regulating Ras.
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PMID:Genetic analysis is consistent with the hypothesis that NF1 limits myeloid cell growth through p21ras. 794 98

Patients successfully treated for a malignancy with cytotoxic therapy have an increased risk of developing secondary myelodysplasia (MDS) and acute myeloid leukemia (AML). We report a patient in remission from Hodgkin's disease (HD) who remains hematologically normal 4 years after combination chemotherapy, but who has biological and genetic abnormalities characteristic of myelodysplasia. X-inactivation analysis using a 5' phosphoglycerate kinase (PGK) probe demonstrates polyclonal hematopoiesis, but cytogenetic analysis reveals a clonal population with a minority of metaphases having a 7q-deletion. NRAS mutations are not detectable 1 year after treatment, but are present in two separate clones (at codons 12 and 15) analyzed by single-stranded conformational polymorphism (SSCP), followed by cloning and sequencing 4 years after treatment. The presence of an activated NRAS with the same codon 12 mutation was independently confirmed by the nude mouse tumorigenicity assay. In vitro peripheral blood granulocyte-macrophage colony-forming units (CFU-GM) have changed from normal to undetectable levels while erythroid burst forming units (BFU-E) were significantly reduced on two occasions during the period of observation. These abnormalities are characteristic of MDS. Continued clinical follow-up will determine whether these evolving genetic and biological abnormalities pre-date the onset of clinical and morphological features of MDS.
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PMID:Non-dysplastic myelodysplasia? 815 65

Thirty Indian patients diagnosed as having primary myelodysplastic syndrome as per the French-American-British classification were investigated, on admission, for the frequencies of nonrandom karyotype abnormalities, sister chromatid exchange, and point mutations of the RAS oncogene. Successful karyotype analysis was possible in 24 patients, of whom 9 (37.5%) showed nonrandom karyotypic changes. Anomalies of chromosomes 5, 7, and 8 were detected in their bone marrow (BM). In addition, two new anomalies, del(8)(q22) and +19, were observed for the first time in our series. Six MDS patients were studied for SCE in either BM or peripheral blood. These data revealed a normal SCE incidence. Of the 10 MDS patients studied for point mutations of NRAS 12 and 61 and KRAS 12 and 61, one patient exhibited a base substitution at position 1 of the 12th codon of the KRAS gene. These data, gathered for the first time on the Indian patients, throw some light on the nature of genetic changes in MDS of our country.
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PMID:Analysis of karyotype, SCE, and point mutation of RAS oncogene in Indian MDS patients. 843 11

We performed longitudinal analyses of chromosomes and studied the configuration of NRAS, TP53, NF1, and cFMS genes in 70 patients with myelodysplastic syndrome(MDS). The NRAS mutations were detected in 6 patients(9%) at codons 12 or 13. The TP53 mutations were found in 10 patients(14%) in exons 4 through 8. Longitudinal studies revealed that the NRAS mutation was a late-appearing event, while the TP53 mutations were detectable at the presentation of MDS. No patients had both NRAS and TP53 mutations, simultaneously. NF1 and cFMS genes showed any mutational event among these 70 patients. Patients with a TP53 mutation had a significantly shorter survival time than those with an NRAS mutation or those without NRAS or TP53 mutation. However, patients who showed an NRAS mutation had a shorter survival time once the mutation emerged, similar to that of patients with a TP53 mutation.
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PMID:Genetic aberrations in the development and subsequent progression of myelodysplastic syndrome. 920 48

Translocations of the MLL gene at chromosome band 11q23 are the most common cytogenetic alterations in de novo leukemia in infants and in leukemia related to chemotherapy with DNA topoisomerase II inhibitors. Experiments on knock-in mice suggest that additional mutational events may by required for full leukemogenesis. Therefore, we used single-strand conformation polymorphism analysis and an allele-specific restriction enzyme assay to investigate the frequency of KRAS and NRAS mutations in 32 pediatric leukemias with translocation of the MLL gene. Of 25 de novo cases, 13 were acute lymphoblastic leukemia (ALL), 10 were acute myeloid leukemia (AML), and 2 were biphenotypic. Three secondary leukemias were AML, 1 was biphenotypic, 1 was ALL, and 2 were diagnosed as myelodysplasia. The frequency of RAS mutations was 2 of 10 in de novo AML. Both mutations occurred in infant monoblastic variants. RAS mutations were otherwise absent in this series. This is the first report of congenital leukemias where translocation of the MLL gene and RAS mutation coexist. The frequency of RAS mutations in de novo AMLs with MLL gene translocations is similar to that in other forms of AML, but RAS mutations play a limited role in lymphoid and treatment-related leukemias with similar translocations.
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PMID:RAS mutations in pediatric leukemias with MLL gene rearrangements. 952 5

Chromosomal translocations involving the genes encoding the alpha and beta subunits of the Pebp2/Cbf transcription factor have been associated with human acute myeloid leukemia and the preleukemic condition, myelodysplasia. Inv(16)(p13;q22) fuses the gene encoding the beta subunit of Pebp2 to the MYH11 gene encoding a smooth muscle myosin heavy chain (Smmhc). To examine the effect of the inv(16)(p13;q22) on myelopoiesis, we used the hMRP8 promoter element to generate transgenic mice expressing the Pebp2betaSmmhc chimeric fusion protein in myeloid cells. Neutrophil maturation was impaired in PEBP2betaMYH11 transgenic mice. Although the transgenic mice had normal numbers of circulating neutrophils, their bone marrow contained increased numbers of immature neutrophilic cells, which exhibited abnormal characteristics. In addition, PEBP2betaMYH11 inhibited neutrophilic differentiation in colonies derived from hematopoietic progenitors. Coexpression of both PEBP2betaMYH11 and activated NRAS induced a more severe phenotype characterized by abnormal nuclear morphology indicative of granulocytic dysplasia. These results show that PEBP2betaMYH11 can impair neutrophil development and provide evidence that alterations of Pebp2 can contribute to the genesis of myelodysplasia.
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PMID:The PEBP2betaMYH11 fusion created by Inv(16)(p13;q22) in myeloid leukemia impairs neutrophil maturation and contributes to granulocytic dysplasia. 975 56

Cytogenetic analysis was performed in 60 patients with primary myelodysplastic syndromes--diagnosed, treated, and followed in our department. In 41 cases, the presence of the NRAS mutation was also evaluated. The aim of this study was to evaluate the prognostic value of chromosomal abnormalities and NRAS mutation. The median age of the patients was 67 years (18-88 years), and the French-American-British classification was as follows: refractory anemia 26, refractory anemia with ring sideroblasts 4, refractory anemia with excess of blast cells 15, refractory anemia with excess of blast cells in transformation 3, and chronic myelomonocytic leukemia 12. Survival analysis was performed for the patients with a normal (n = 35), an abnormal (n = 25) karyotype and with a single (n = 15) or multiple (n = 10) cytogenetic abnormalities. Abnormal karyotypes were detected in 25 of the 60 patients (41.6%). Fifteen of these patients had a single and 10 had two or more lesions. The median survival of the patients with a normal (33.1 months) and with an abnormal (36.5 months) karyotype was not significantly different. Patients with multiple lesions had a reduced median survival compared with patients with single anomalies (19.2 versus 39.7 months, p = 0.5). Patients with an abnormal karyotype progressed to acute leukemia more frequently compared with patients without lesions (36 versus 28.6%, p = 0.5). NRAS mutation was detected in 2 of 10 CMMoL patients studied and in none of the 31 patients with other types of myelodysplastic syndrome. Marrow blasts more than 10% significantly affected survival.
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PMID:Cytogenetic analysis and RAS mutations in primary myelodysplastic syndromes. 1034 48


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