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

Activating ras mutations are frequent (25-60%) in chronic myelomonocytic leukemia (CMML) and in acute myeloid leukemia (AML) (30%), in contrast to chronic myeloid leukemia (CML) in which the incidence is very low (0-3%). This might reflect that the leukemic cell in CML is at a level of differentiation in which ras gene activation is not involved or, alternatively, might be due to the presence in CML of the bcrlabl fused gene. We have analyzed the presence of point mutations in codons 12, 13, 59, 61 and 63 of N-, K-, and H-ras genes, in 26 cases of Philadelphia-chromosome-positive, bcrlabl-positive acute leukemia (Ph+ AL), and in eight CMML cases by using the polymerase chain reaction. Aberrant ras genes were detected in a single Ph+ AL case, and in four out of eight CMML patients. The Ph+ AL showing altered ras allele had an unusual point mutation in H-ras gene, substituting leucine for glutamine. This mutation has not been previously found in any hematological disease. Our findings suggest that ras mutations are probably not involved in the pathogenesis of those leukemias in which blast cells contain bcrlabl oncogene activation.
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PMID:Low frequency of ras oncogene mutations in Philadelphia-positive acute leukemia and report of a novel mutation H61 Leu in a single case. 158 96

DNA from white blood cells from healthy controls demonstrates a restriction fragment length polymorphism (RFLP) of the Ha-ras oncogene locus after cleavage with the restriction enzymes BamH I or MspI plus HpaII, representing frequent and rare alleles. We have studied the RFLP of 15 patients with B-cell chronic lymphocytic (CLL) and of 16 patients with chronic myelogenous leukemia (CML). As in healthy controls the RFLP in the leukemic cells indicates the occurrence of frequent and rare Ha-ras alleles. But rare alleles are not more frequent in the patients than in the healthy control group. The frequency of rare Ha-ras alleles also does not differ between chronic lymphocytic and chronic myelogenous leukemia. While rare alleles of this oncogene locus occur in CML and CLL as frequently as in healthy controls, they do not reflect an inherent increased risk for chronic leukemia in man.
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PMID:Polymorphism of the human Ha-ras oncogene locus in chronic lymphocytic and chronic myelogenous leukemia. 168 29

Twenty-nine patients with acute myelocytic leukemia (AML) and 14 patients with Philadelphia chromosome-positive chronic myelocytic leukemia (CML) were analyzed to detect the presence of mutations in their ras genes by the polymerase chain reaction and oligonucleotide hybridization methods. Deoxyribonucleic acid (DNA) isolated from blood or bone marrow samples was screened for mutations in codons 12, 13 and 61 of N-ras and in codons 12 and 61 of K-ras and H-ras. We detected mutations of the ras gene in 7 patients with AML (7/29), all in N-ras. The mutations were 3 GGT- greater than GAT transitions in codon 12, 1 GGT- greater than TGT transition in codon 13, and 3 CAA- greater than AAA transitions in codon 61. No correlation has been observed between French-American-British subtypes and the incidence of N-ras mutation, nor between cytogenetic changes and the incidence of N-ras mutation. All ras gene mutations detected by the oligonucleotide hybridization method were further confirmed by direct sequencing. No mutations were detected in ras genes in samples from the 14 Philadelphia chromosome-positive CML patients (12 in chronic phase, 2 in blastic phase). These findings are in line with previous results indicating that ras gene mutations in the codons tested play only a small role in the tumorigenesis of CML.
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PMID:Mutation analysis of the ras gene in myelocytic leukemia by polymerase chain reaction and oligonucleotide probes. 168 80

The first clear cut association of an oncogene with a specific cancer is the c-abl translocation in chronic myelogenous leukemia and acute lymphocytic leukemia; it has been observed in 90% of CML cases examined. This is the major contributing factor to its being the target of the first oncogene-based FDA-approved diagnostic test. Although the role of the abl translocation in the tumorigenic process is not yet understood, it is clear that somehow it must be causally related to the disease, and thus is an ideal target for a diagnostic test. The association of this oncogene with a specific cancer is the model on which all others may be based in the future. Second generation tests could easily include PCR on mRNA, and/or in situ hybridization, both of which could be performed using blood samples. Both methods would provide a faster means of testing a large number of cells, however, the methodologies must be improved through automation and computer-aided image analysis, respectively, in order to become useful routine tests. Both neu and epidermal growth factor receptor (EGFR) appear to have a close correlation between overexpression of the gene product and outcome of disease in breast cancer; valuable information for prognosis of the disease. And again, although the actual mechanism of action of these molecules and how this relates to the tumorigenic process is not yet known, it is believed from the very nature of the molecules that they must in some way contribute to the progression of the disease. In both cases, the protein products are overexpressed in tissue, and in the case of Neu, it appears as through at least some of the patients have a Neu-related protein in their serum. These molecules present relatively easy targets for the development of diagnostic/prognostic assays, as antibodies are easily made and can be incorporated into a variety of assay formats. Current assays available, an ELISA for Neu and a radio-ligand binding assay for EGFR, are highly sensitive, reproducible and relatively easy to perform. Only the ELISA is commercially available, however, and hence allows for easy comparison between laboratories. An abvious step towards the routine measurement of EGFR then is the development of a comparable commercially available test. An improvement for both types of assay would be the incorporation of an internal control to gauge the cellular component of the tissue samples that are tested. The outcome of the applications of myc and ras to cancer diagnostics is not so easily predictable, with a couple of exceptions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Diagnostic utility of oncogenes and their products in human cancer. 168 91

The increased activity in cancer cells of inosine 5'-monophosphate dehydrogenase (IMP DH, EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, was suggested as a sensitive target for chemotherapy. Tiazofurin (NSC 286193), through its conversion to the active metabolite, thiazole-4-carboxamide adenine dinucleotide (TAD), is a strong inhibitor of IMP DH. In our clinical trial, tiazofurin caused return to the chronic phase in patients with chronic granulocytic leukemia in blast crisis (Tricot, G.; Jayaram, H.N.; Weber, G.; Hoffman, R. Tiazofurin: Biological effects and clinical uses. Int. J. Cell Cloning 8:161-170; 1990). In K562 human leukemic cells, tiazofurin down-regulated the expression of c-Ki-ras and c-myc oncogenes, which was followed by induced differentiation. We now report down-regulation by tiazofurin of the c-Ki-ras oncogene in a patient with chronic granulocytic leukemia in blast crisis. A single tiazofurin infusion (2,200 mg/m2) on days one and two decreased IMP dehydrogenase activity (the apparent t1/2 was 30 min), GTP concentration (the apparent t1/2 was 6 hr), and expression of ras (the apparent t1/2 was 8 hr) and c-myc (the apparent t1/2 was 38.5 hr) oncogenes in the leukemic cells. No further tiazofurin was given, because on days three and four the chemotherapeutic impact became evident in a tumor-lysis syndrome and the blast cells were cleared from the periphery by day five. The decrease in IMP DH activity, GTP concentration, and expression of c-Ki-ras oncogene were early markers of the successful chemotherapeutic impact of tiazofurin in a patient with chronic granulocytic leukemia in blast crisis.
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PMID:Tiazofurin down-regulates expression of c-Ki-ras oncogene in a leukemic patient. 170 12

Seventy five radiation-related leukemia patients in Hiroshima including 16 patients exposed to more than one Gray were cytogenetically examined. Statistical analysis of data on the frequencies of chromosomal aberrations in the survivor groups according to bone marrow doses by DS86 estimation revealed that the heavily exposed group tended to have significantly higher aberration rates compared to the non-exposed group. Furthermore, the chromosomal aberrations in the survivors were observed to be of a more complex nature and had the characteristic findings of secondary leukemia. These observations therefore suggest that patients with a history of heavy exposure to atomic bomb radiation had leukemic cells originating from a stem cell which had been damaged by irradiation at the time of the bombing as well as cells involved in complex chromosome abnormalities. Molecular biologic studies on ras genes in acute and chronic leukemias and the bcr gene in chronic myelocytic leukemia were performed in exposed and non-exposed groups. So far, no distinctive differences have been observed in the frequency and sites of point mutations in N- and K-ras genes or in the rearrangement of the bcr gene. Further, retrospective analysis using DNA from leukemia patients who developed this disease in the early period from atomic bomb radiation exposure would be useful for the elucidation of the mechanisms of radiation-induced leukemia.
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PMID:Cytogenetic and molecular changes in leukemia among atomic bomb survivors. 182 62

An overview was presented of our approach of inhibition of de novo and salvage pathways in pyrimidine and purine metabolism. 1. Combination of acivicin, an inhibitor of de novo biosynthesis, and dipyridamole, a transport inhibitor, provided synergistic cytotoxicity in hepatoma and colon carcinoma cells. 2. AZT, a competitive inhibitor of the salvage enzyme, thymidine kinase, and 5-FU or MTX provided synergistic cytotoxicity in hepatoma 3924A. In human colon carcinoma HT-29 cells AZT and methotrexate yielded synergistic cytotoxicity and thymidine and hypoxanthine together provided protection from the action of these drugs. 3. These observations are significant because in rat hepatoma 3924A and in human cell lines HT-29, HL-60 and K562 thymidine kinase activity was 16- to 67-fold higher than that of dTMP synthase. Therefore, inhibition of dTMP synthase activity alone may provide poor responses because the salvage pathways can circumvent this block. 4. In leukemic patients treated with tiazofurin, an inhibitor of IMP dehydrogenase, the rate-limiting enzyme of GTP biosynthesis, and with allopurinol, which inhibits GPRT activity through raising plasma hypoxanthine levels, synergistic therapeutic results were obtained. The responses in sensitive patients entailed a decrease in IMP dehydrogenase activity and GTP concentration in leukemic cells and down-regulation of the ras and myc oncogenes. The down-regulation of the ras oncogene by tiazofurin through the decrease of GTP concentration has now been shown in K562, HL-60 and hepatoma cells and in patients with chronic granulocytic leukemia in blast crisis. Tiazofurin may be useful in studies on selective depression of the expression of the ras oncogene. 5. In 27 consecutive patients 50% responded positively to tiazofurin treatment. From this group, 10 out of 12 patients (83%) with chronic granulocytic leukemia in blast crisis responded to tiazofurin treatment.
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PMID:Regulation of de novo and salvage pathways in chemotherapy. 187 99

We have carried out the molecular and cell-biological analysis on Ph1-positive leukemias in this study. Five out of nine Ph1-positive ALL cases showed molecular rearrangement within the classical bcr sequence (or M-bcr), similar as those in 47 CML cases. We examined 4 cases of Ph1-positive ALL presenting no rearrangement of M-bcr and found that, in 2 of 4 cases, one showed the breakpoint in a 5 kb segment of the bcr gene first intron (bcr-2) and the other in bcr-1, 16 kb upstream of bcr-2. Ph1-positive ALL frequently showed biphenotypical or biclonal phenotypes of myeloid and lymphoid lineages. Furthermore, we demonstrated the ability of two Ph1-positive ALL cell lines to differentiate into monocytic lineage in vitro, thus suggesting the possibility that these Ph1-positive ALL cells might reside on the stage of multipotent stem cell along the hematopoietic cell differentiation. Two out of 31 CML cases showed the mutations of the ras genes by the polymerase chain reaction; one case in the crisis phase and the other in the chronic phase. However, no mutations of the fms genes was detected. Two cases in the crisis phase of 24 CML patients (11 cases in the chronic phase and 13 cases in the crisis phase) contained rearrangements of the p53 gene by Southern analysis. Furthermore, the transcriptional alteration was found in 2 CML-BC and 2 CML-BC derived cell lines' samples, suggesting a important role of the p53 gene in the transformation of CML into the crisis phase.
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PMID:[Rearrangement and expression of bcr-abl genes in CML and ALL]. 189 Jul 38

Usefulness of DNA analysis in diagnosis of hematopoietic malignancy was discussed. Examination on the presence of rearrangement in immunoglobulin (Ig) and T cell receptor (TCR) was the first DNA analysis used for clinical diagnosis of lymphoid malignancy to determine the cell-lineage and clonality of proliferating lymphoid cells. One point mutation in ras oncogene has also been used to detect residual leukemic cells as well as diagnosis of the early relapse of leukemia, although not all leukemic cells have this mutation. Presence of BCR-abl fused gene is a genetic marker for Ph1 chromosome. Analysis of BCR-abl gene has made it possible to diagnose the Ph1 ALL and masked Ph1 CML. Development of PCR technique markedly increased the possibility for the use of DNA analysis in clinical medicine. In addition to Ph1 chromosome, various chromosomal abnormalities resulted in a reciprocal translocation between Ig or TCR gene and other genes in various lymphoid malignancies, such as Burkitt lymphoma and follicular lymphoma. These translocations can be analyzed by Southern hybridization and used for clinical diagnosis.
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PMID:[DNA diagnosis of human cancers: lymphoid malignancies and leukemia]. 198

Previous studies have shown that approximately 30% of adult acute myeloid leukaemias and 20% of adult acute lymphoid leukaemias contain point mutated ras oncogenes. In order to assess whether ras oncogenes are also involved in childhood leukaemias, we have used polymerase chain reaction (PCR) amplification and synthetic oligonucleotide probes to study the nature and frequency of ras gene mutations in childhood leukaemias, concentrating largely on the acute myeloid leukaemias (AML). Thirty-four childhood presentation AML DNAs were screened for mutations in and around codons 12, 61 and 117 of N-, K- and H-ras. Eight of these samples (24%) contained ras mutations. As in the adult disease, the gene predominantly involved was N-ras (6/8), with occasional activation of K-ras (2/6). The most common base change was a G----A transition at codon 12 or 13 (4/8). Of the patients with mutant ras, 4/8 were diagnosed as AML FAB subtype M5. Five of the 34 childhood AMLs analysed displayed abnormalities of chromosome 7. However, none of these cases contained a mutant ras gene. One AML patient was studied at relapse, 14 months after initial presentation. The presentation mutation (N61p3) was not detectable, although a new mutation (N13Cys) was readily identified. This observation extends our original finding with presentation and relapse samples of adult AML, in which it was uncommon for the relapse sample to contain the same ras mutation as the presentation DNA. In addition, two out of five patients diagnosed as juvenile CML, were found to harbour mutant ras.
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PMID:Analysis of ras gene mutations in childhood myeloid leukaemia. 201 56


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