Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We performed a longitudinal analysis of the karyotypes and N-ras gene configuration of bone marrow cells in 35 patients with myelodysplastic syndrome (MDS). Karyotypic evolution was found in eight patients, and was associated with disease progression, including leukemic transformation, in all the patients. We identified N-ras mutations in six patients, using a polymerase chain reaction (PCR) technique, in which oligonucleotide primers were constructed with induced mismatches, followed by endonuclease digestion. Direct sequencing confirmed single base substitutions at codon 12 in two patients and at codon 13 in four. The incidence of N-ras gene mutations was significantly higher in the karyotypically evolved group (five of eight patients) than in the stable group (one of 27 patients). All of five patients harboring both karyotypic evolution and an N-ras mutation showed concomitant disease progression to overt leukemia or refractory anemia with excess of blasts in transformation (RAEB-T). Two of four patients with either karyotypic evolution or N-ras mutation and six of 26 patients without any of these alterations also progressed to overt leukemia. Our results indicate that the accumulation of these genetic alterations is closely associated with leukemic transformation of MDS, although other genetic alterations may also play a key role in the remaining patients.
Leukemia 1994 Aug
PMID:N-ras mutation and karyotypic evolution are closely associated with leukemic transformation in myelodysplastic syndrome. 805 69

Patients with Fanconi anemia (FA) have an extraordinary predisposition to acute myelogenous leukemia (AML). The genetic mechanisms underlying the neoplastic transformation of FA hematopoietic cells are unknown. In this study, we have investigated the molecular features of hematopoiesis in the course of FA at different stages of the disease, including aplastic anemia, myelodysplastic syndrome (MDS), and AML. The analysis focused on defining the clonality status of FA hematopoiesis as well as the putative involvement of N-ras, a dominantly acting oncogene, and p53, a tumor suppressor gene, which are known to play a role in human hematopoietic tumors. Clonality of hematopoiesis was assessed by testing X-chromosome inactivation at the DXS255 locus, which displays different methylation patterns according to the activation status of the corresponding X homolog. Five out of seven FA cases analysed for clonality displayed monoclonal hematopoiesis, including one case at the aplastic anemia stage, three cases with MDS and one with AML. Mutations of the N-ras and p53 genes were studied by a combination of single strand conformation polymorphism (SSCP) analysis and direct sequencing of the PCR product in the bone marrow and/or peripheral blood of 18 FA patients (seven with aplastic anemia, seven with MDS, four with AML). Only normal N-ras and p53 sequences were detected in all cases analyzed. These results suggest that monoclonal hematopoiesis is a frequent finding in the course of FA and may precede the onset of neoplasia in some cases. The genetic mechanisms underlying FA-associated leukemogenesis appear to be independent of N-ras and p53 mutations, which are relatively frequent events in myeloid tumors associated with other hematologic disorders.
Leukemia 1994 Aug
PMID:Clonality studies and N-ras and p53 mutation analysis of hematopoietic cells in Fanconi anemia. 805 73

Myelodysplastic syndrome (MDS) has been thought to be an identifiable early stage in multistep leukemogenesis. Considerable numbers of patients with MDS eventually develop acute myelogenous leukemia (AML), which is very much more difficult to manage than typical denovo AML. There are several differences in both the clinical and biological behavior of AML with and without prior MDS. We have established an unique long-term bone marrow culture (LTBMC) system which allows abnormal cells to grow in preference to normal cells, based on the method originally described by Dexter et al. Leukemic transformations occur more frequently in MDS patients with abnormal karyotypes, and particularly those with multiple abnormalities. New cytogenetic abnormalities were occasionally observed at the time of transition to AML. We have applied this LTBMC system for cytogenetic and molecular studies on the leukemic transformation from MDS. Among the 32 patients with MDS studied thus far, novel abnormal karyotypes were detected during the LTBMCs in 15 patients. Furthermore, 6 out of 23 novel karyotypes detected during the in-vitro cultures emerged in vivo, one to 11 months later in 4 patients. In addition, point mutation of the N-ras proto-oncogene was observed in 3 of 18 cases. The signal of the dot-blot hybridization was increased in one examined case after 2 weeks in culture. Thus, this LTBMC system may provide some promising information with respect to understanding the multistep process from the preleukemic stage to the development of overt leukemia as well as its prognostic relevance.
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PMID:Application of long-term bone marrow cultures for studying the leukemic transformation of myelodysplastic syndromes. 812 6

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.
Leukemia 1994 Jun
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 frequency of simultaneously detecting N-ras and p53 gene mutations was studied in leukaemia cells of patients with acute myeloid leukaemia (AML) or with myelodysplastic syndrome (MDS). Using in vitro DNA amplification followed by oligonucleotide hybridization analysis, 45 AML and six MDS patients were screened for activating mutations in codons 12, 13 and 61 of N-ras. Ten of them (eight AML and two MDS) were found positive. These 10 patients and 10 others without activating N-ras mutation were further analysed by direct sequencing of the amplified exons for p53 mutations and for atypical N-ras mutations. Beside the activating mutations in the N-ras gene, no additional transforming or nontransforming mutations could be detected in the N-ras. However, exon 7 of p53 was mutated in two AML patients without activating N-ras mutation. These data show that p53 mutations occurred with half the frequency of N-ras mutations in AML and that no positive correlation could be found between the onset of mutations in N-ras and p53 genes.
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PMID:Occurrence of point mutations in p53 gene is not increased in patients with acute myeloid leukaemia carrying an activating N-ras mutation. 821 95

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

Point mutations in codons 12, 13, and 61 of N-ras have consistently been reported in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) using a variety of techniques. Recently mutations in codons 301 and 969 of c-fms, preferentially involving TAT-to-TGT at codon 969, have also been identified in these disorders by allele specific oligonucleotide (ASO) hybridization. We have developed allele specific restriction analysis (ASRA) protocols for the detection of point mutations in the critical codons of these genes. ASRA involves enzymatic digestion of polymerase chain reaction (PCR)-induced restriction sites which are specific for normal but not mutant alleles. A total of 11 N-ras mutations were observed in 10 out of 46 AML patients, consistent with the reported frequency of N-ras mutations when alternative techniques of comparable sensitivity are used. In contrast, c-fms point mutations were not detected in a similar number of patients with AML, including 39 studied for mutations in both N-ras and c-fms, and this difference is statistically significant (p < 0.003). A more sensitive technique (ASRA + ASO hybridization) also failed to detect TAT-to-TGT substitutions at codon 969 in a subgroup of M4-AML patients considered to be at greatest risk of harboring c-fms mutations. This study suggests that c-fms mutations at codons 301 and 969 are not important in the pathogenesis of AML in the vast majority of patients.
Leukemia 1993 Jul
PMID:c-fms point mutations in acute myeloid leukemia: fact or fiction? 832 Oct 48

The protein smg p21A/Krev-1/rap 1A was identified as a ras p21-like small G-protein, having the ability to revert v-Ki-ras transformed NIH 3T3 fibroblasts. The expression level of smg p21A and ras p21s during phorbol ester-induced differentiation of HL-60 and MEG-01 cell lines was analyzed by immuno- and Northern blotting. In both cell lines, levels of smg p21 and ras p21s increased quickly in early phase of differentiation along with the appearance of differentiation phenotypes. They increased 3-4 fold on days 1-2, then decreased gradually. The increasing smg 21 mRNA levels also corresponded with that of products. Among ras mRNAs, Ha-ras and N-ras transcripts increased somewhat faster than smg 21. These small G-proteins may play closely related roles in the differentiation of these leukemia cell lines.
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PMID:Up-regulation of small GTP-binding proteins smg P21A and ras P21S during TPA-induced differentiation of human leukemia cell lines. 842 89

We have screened mutations of the N-ras gene at codons 12, 13, and 61 in leukemia cells obtained from 100 patients with acute myeloid leukemia (AML), and found mutated N-ras alleles in 9 patients. We further analyzed the polyclonality of multiple N-ras gene mutations in 4 AML patients. One patient, who had the monoclonal karyotype, t(11;17), had two types of double missense mutations at codons 13 and 61 in the same allele. Each of the remaining three patients, one of whom had t(15;17) with a monoclonal rearrangement of the retinoic acid receptor alpha and PML genes, carried two missense mutations in a relatively small population of leukemia cells. We have demonstrated that multiple clonality of the N-ras gene is occasionally observed in leukemia with a monoclonal karyotype. These findings indicate that the N-ras mutations may not always be characterized simply by an accumulative process and that the activated N-ras gene alone is not sufficient to cause leukemia.
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PMID:Clonal analysis of multiple point mutations in the N-ras gene in patients with acute myeloid leukemia. 851 4

We report a patient with acute myelomonocytic leukemia (AMMoL) who showed two independent point mutations of the N-ras gene at codons 12 and 13. Longitudinal analysis revealed that one mutation at codon 13 was detectable throughout his disease course and the other at codon 12 emerged as a second mutation 14 months after the diagnosis was made, at the refractory stage. Cloning to vector and subsequent sequencing confirmed that these mutations occurred in different alleles. Chromosome findings showed a simple abnormal karyotype at presentation and further karyotypic aberrations during his disease course, concomitantly with the second mutation of the N-ras gene. These findings revealed a close relationship among the disease progression, karyotypic evolution and a newly-appearing N-ras mutation.
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PMID:Double mutations of the N-ras gene in a patient with acute myelomonocytic leukemia. 854 9


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