Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations within N-ras oncogene codons 12, 13, and 61 occur in approximately 25-30% of patients with acute nonlymphocytic leukemia and at a lower frequency (6-20%) in patients with acute lymphocytic leukemia. Moreover, N-ras mutations have been described in patients with chronic myeloid leukemia (CML) in blast crisis but have not been observed during the chronic phase of the disease. In view of the morphological and clinical similarities between acute leukemia and the blast crisis of CML, the question was raised whether the presence of N-ras mutations is associated with the phenotype of acute leukemia. We investigated leukemic cells from 100 patients with CML for the presence of N-ras mutations in the mutational hot spot codons. The cases analyzed included 87 diagnosed with different types of blast crisis and 13 cases in accelerated or chronic phase of the disease. Fragments from N-ras exons I and II containing the codons of interest were amplified by polymerase chain reaction and analyzed for the presence of point mutations by three different technical approaches, including specific oligonucleotide hybridization, direct sequencing, and single-strand conformation polymorphism analysis. N-ras mutations were not detected in any of the CML patients investigated. Only one patient, in whom the initial diagnosis of CML-blast crisis had been revised to chronic myelomonocytic leukemia, displayed an N-ras mutation within codon 13. Our data strongly suggest that N-ras mutations do not play a role in myeloid or lymphoid blast crisis of CML.
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PMID:Absence of N-ras mutations in myeloid and lymphoid blast crisis of chronic myeloid leukemia. 803 17

Juvenile chronic myelogenous leukemia (JCML), a myeloproliferative disorder of childhood, is distinct from adult-type chronic myelogenous leukemia (CML) and bears resemblance to chronic myelomonocytic leukemia (CMMoL). Since mutations in the N-ras gene have been found at high frequencies in CMMoL, but only rarely in CML, we analyzed mutations activating the N-ras gene in 20 patients with JCML. We used the strategy for analysis of gene mutations based on in vitro DNA amplification by polymerase chain reaction (PCR) followed by single-strand conformation polymorphism (SSCP) analysis and/or direct sequence analysis. Nucleotide sequence analysis showed single nucleotide substitutions involving codons 12, 13, or 61 in six of 20 patients (30%). Four of six patients with mutations were in chronic phase and the other two in blast crisis, indicating no apparent correlation with disease stage. Most of the patients with mutations were in the older age group with poor prognosis, although one patient in the younger age group also harbored the mutation. These data suggest that N-ras gene mutations may be involved in the pathogenesis and/or prognosis of JCML and provide further evidence that JCML is an entity distinct from CML.
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PMID:Mutations of the N-ras gene in juvenile chronic myelogenous leukemia. 816 90

We investigated mutations in the GTPase activating protein-related domain of the neurofibromatosis type 1 gene (NF1-GRD) and its expression in each phase of chronic myelogenous leukemia (CML). Samples from 45 cases in chronic phase (CP), 41 in acute phase, and four CML cell lines were examined for mutations in the NF1-GRD by single-strand conformation polymorphism (SSCP) analysis and allele specific restriction analysis (ASRA). No mutations were detected in the exon where frequent mutations have recently been reported in human tumors, namely the FLR exon. We also examined for point mutations of the N-ras gene but found no mutations either. In 23 samples from CML cases and four CML cell lines, expression of two types of the NF1-GRD transcripts, type I and type II, were examined by NF1-GRD-specific polymerase chain reaction-based densitometric analysis and by the quantitative assay with coamplification of the NF1-GRD and beta-actin transcripts. Consequently, although expression level of type I transcripts varied among the samples, type II expression was increased in CML cell lines and a minor increase in type II expression was observed in the samples in acute phase compared with CP. However, this difference in type II expression between CP and acute phase was so small that changes of NF1-GRD transcripts as well as NF1-GRD or N-ras mutations might not be responsible for the progression of CML.
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PMID:Analysis of mutations and expression of GAP-related domain of the neurofibromatosis type 1 (NF1) gene in the progression of chronic myelogenous leukemia. 820 76

The "constitutive" expression of the c-myc gene was detected in leukemia cells obtained from 4 patients with an acute myeloid leukemia, 3 with chronic myeloid leukemia and 1 with a myelodysplastic syndrome. Studies were undertaken to determine whether or not the myc gene was rearranged or mutated in exon I within a 3'Pvu II region, a transcriptional attenuation site. Studies to explore the possibility of a point mutation in the N-ras gene were also conducted. No abnormalities were detected in either gene. Studies should be undertaken evaluating the possibility of a post-transcriptional mechanism, such as alteration of RNA stability, which could be responsible for the constitutive expression of c-myc gene.
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PMID:Analysis of the c-myc and N-ras genes in acute myelogenous leukemia cells which manifest the constitutive expression of the c-myc gene. 831 7

The malignant diagnosis of a haematological disorder can in most cases be made by clinical signs and routine microscopic examination. However, it has become necessary to characterize the malignant clone with various markers, which give either knowledge of the prognosis of the disease or give tools for the laboratory follow up of the patient. In lymphatic diseases there are excellent markers of clonality. On the contrary in myeloid malignancies the few well characterized markers are mostly helpful in the clinical management of rare myeloid subgroups. The aim of our project has been to develop methods for laboratory monitoring of myeloid diseases by two major approaches 1) detection of methylation alterations in the short arm of chromosome 11 and 2) novel approaches for sensitive point mutation detection. The short arm of chromosome 11 has areas where the DNA becomes hypermethylated in acute leukemias and lymphomas. In this chromosomal area the calcitonin gene serves as a good marker for methylation alterations due to several CpG sites in the 5'area of the gene. Even if the gene is normally methylated in most cases of chronic myeloid leukemia (CML), we have found that the hypermethylation of the calcitonin gene marks progression of CML and precedes any other signs of acceleration with several months. The point mutations of certain proto-oncogenes, such as the N-ras gene, are attractive markers for detecting residual diseases after chemotherapy of high malignant haematological disorders. However, conventional methods for detecting point mutations have been both insensitive and cumbersome, and thus unsuitable for clinical routine laboratories. With the solid-phase minisequencing we can technically easily and accurately detect small quantities of mutated cells.
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PMID:Development of molecular genetic methods for monitoring myeloid malignancies. 832 16

A mutant human N-ras gene (codon 61, C to A substitution) was electroporated into the human leukemic cell line K562, originally derived from a patient with chronic myeloid leukemia (CML) in blast crisis. Despite confirmation of mutant N-ras gene integration and expression, mutant transfected cells exhibited no growth advantage when characterized in suspension cultures and clonogenic assays, and serum deprivation impaired proliferation of both normal and mutant N-ras transfected cells equally. A subclone containing a mutant N-ras gene displayed a proliferation rate and differentiation potential identical to that of non-transfected cells. The failure of N-ras mutations to modify K562 cell behavior is in keeping with the infrequent observation of N-ras mutations in blastic transformation of CML.
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PMID:Characterization of K562 cells following introduction of a mutant N-ras gene. 842 76

Mutations that activate the N-ras oncogene are among the most frequently detected genetic alterations in human acute myeloid leukemias (AMLs), Philadelphia chromosome-negative myeloproliferative disorders (MPDs), and myelodysplastic syndromes (MDSs). However, because N-ras has not been shown to induce these disorders in an in vivo model, the role of N-ras in the evolution of myeloid leukemia is unclear. To investigate the potential of N-ras to induce myeloid leukemia, lethally irradiated mice were reconstituted with bone marrow (BM) cells infected with a retroviral vector carrying activated N-ras. Approximately 60% of these mice developed hematopoietic disorders, including severe MPDs resembling human chronic myelogenous leukemia (CML) or AML with differentiation (French-American-British [FAB] classification M2). Other reconstituted mice succumbed to hematopoietic defects that were pathologically similar to human MDSs. The latter disorders appeared to be due to a myeloid impairment that was demonstrated by enumeration of day-12 colony-forming units-spleen (CFU-S) and by in vitro colony assays. A high level of apoptosis associated with thymic atrophy and peripheral blood (PB) lymphopenia was also evident in N-ras reconstituted mice. Our results are consistent with a model in which antiproliferative effects are a primary consequence of N-ras mutations and secondary transforming events are necessary for the development of myeloid leukemia. This is the first report of an in vivo model for N-ras induced MPD and leukemia.
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PMID:Mutant N-ras induces myeloproliferative disorders and apoptosis in bone marrow repopulated mice. 1006 78

We attempted to detect the bcr-abl fusion gene and ras gene family in CML by the in vitro focus forming assay and the tumorigenicity assay. Eight of 14 chronic phase and both of two blastic phase cases showed transforming activity in the tumorigenicity assay. However, only one chronic phase sample was positive in the in vitro focus forming assay. Among these 10 transformants, we found N-ras activation in one chronic phase, and K-ras activation in another chronic phase case. The bcr-abl fusion gene was activated in one chronic phase and all of the blastic phase cases by the tumorigenicity assay. The present result showed that the bcr-abl fusion gene transfected N1H3T3 cells formed tumors in nude mice in contrast to the in vitro focus forming assay. The bcr-abl fusion gene may play important roles in the progression as well as the pathogenesis of CML.
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PMID:Activation of bcr-abl fusion gene and ras oncogenes in chronic myelogenous leukemia. 2126 77

Mutations that activate ras genes were demonstrated to be associated with certain types of malignancies. Multiple point mutations were predominantly found in the N-ras and occasionally in the K-ras genes. The analysis of 4 MDS, 23 AML and 11 CML patients from Yugoslavia revealed the prevalence of the N-ras mutation (83%) over K-ras mutations (17%). Although the frequencies of the N- and K-ras mutations in these patients were similar to the ones reported for patients from USA and Japan, the N-ras mutational spectra considerably differed. The prevailing type of mutation in patients from Yugoslavia was G-to-T transversion at the first position in the codon 12 of the N-ras gene. This study supports a hypothesis that different geographical and environmental factors may cause the accumulation of different type of point mutations in the same target gene.
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PMID:Distinct spectrum of N-ras mutations in aml and mds patients in yugoslavia. 2160 14


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