Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cells were treated in vitro with oligodeoxyribonucleotide phosphorothioates (ODNs) complementary to sites common to both wild-type and mutant p53 nucleotide sequences. Acute myelogenous leukemia (AML) blasts from peripheral blood were exposed to four different p53 ODNs and showed anti-leukemic effects in suspension culture. This effect continued after removal of the ODN from the medium. Blocking of self-renewal of the leukemic blast stem cells in secondary plating of cells from cloning assays by two of the p53 ODNs was also observed. Control ODNs had no effect on leukemic blasts. Treatment of normal bone marrow cells with the four p53 ODNs did not influence their growth, nor was there any effect by the p53 ODNs on the leukemic cell-line, HL60, that does not express p53. These data suggest that p53 ODNs are selectively toxic to primary myelogenous blasts and may be therapeutically useful in AML.
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PMID:Selective cytotoxicity to human leukemic myeloblasts produced by oligodeoxyribonucleotide phosphorothioates complementary to p53 nucleotide sequences. 816 53

We report the set-up of a denaturant gradient gel electrophoresis (DGGE) assay to screen for mutations in the whole coding sequence of the p53 gene. These DGGE experimental conditions were applied to the analysis of the p53 gene in acute leukemias. Forty adults with acute myelogenous leukemia (AML) and 21 with acute lymphoid leukemia (ALL) were investigated. Eleven of the AML patients were investigated at the time of the initial diagnosis and at relapse. In contrast with most reports based on amplified fragments analyzed by single-strand conformation electrophoresis and focusing on exons 5 to 8, we analyzed the whole coding sequence of the gene. Two of the 40 AML patients displayed a point mutation in exon 7; it was either an A to G substitution that converted Tyr-234 to Cys, or a G to A change that converted Arg-248 to Gln. The screening procedure led to the discovery of several intronic and exonic polymorphisms. These results confirm the low incidence of p53 mutations in acute leukemias and suggest a limited role of the p53 protein in leukemogenesis. The computerized modeling and electrophoresis parameters presented here provide a powerful tool for the exhaustive characterization of p53 mutants in all kinds of malignancies.
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PMID:Exhaustive analysis of the P53 gene coding sequence by denaturing gradient gel electrophoresis: application to the detection of point mutations in acute leukemias. 819 93

Expression of the wild-type p53 gene has an important role in cell differentiation, maturation and apoptosis. Mutation of the p53 gene is associated with tumour development and mutant p53 can promote cell proliferation. Recently wild-type p53 has been demonstrated to exist in two conformational variants: one acting as a suppressor (PAb240-/PAb1620+) and one as a promoter (PAb240+/PAb1620-) of cell proliferation. We have analysed the expression of p53 by flow cytometry in blast cells from 34 patients with acute myeloblastic leukaemia in relationship to the proliferation characteristics of these cells in a clonogenic assay. Blasts from three out of 34 patients did not express p53 using the antibodies: PAb421, PAb1801, PAb240 and PAb1620. The remaining 31 samples expressed p53 detected by PAb240 which recognises mutant p53 and is predicted to recognise wild-type p53 in the promoter conformation. Blasts from 19 out of 31 cells which expressed PAb240 co-expressed PAb1620, expression of PAb1620 was associated with non-autonomous growth in vitro. In contrast, the majority of blasts with the p53 phenotype of PAb240+/PAb1620- or which lacked p53 expression exhibited autonomous growth characteristics in vitro. Furthermore expression of PAb1620 in blasts with autonomous growth cells could be detected following growth inhibition using monoclonal antibodies against autocrine growth factors. Our data demonstrate that in AML cells, p53 conformation is related to the growth characteristics of the cells and is regulated by either exogenous or autocrine haematopoietic growth factors.
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PMID:Expression of different conformations of p53 in the blast cells of acute myeloblastic leukaemia is related to in vitro growth characteristics. 821

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

p53 overexpression was studied immunohistochemically in paraffin-embedded bone marrow biopsies using a recently described technique for antigen retrieval based on microwave oven heating of paraffin sections. Using a monoclonal antibody (PAb1801) that reacts with human cellular p53, nuclear staining was detected in 7/11 (63%) therapy-related myelodysplastic syndromes and in 3/4 (75%) therapy-related acute myeloid leukemias. Conversely, staining for p53 was seen only in 9/40 (22%) cases of "primary" hematologic conditions (P < 0.007); these included myelodysplastic syndromes [#2], acute myeloid leukemia [#4], and chronic granulocytic leukemia in accelerated phase or blast crisis [#3]. Biopsies of normal controls and of chronic granulocytic leukemia in stable phase were consistently p53(-). Nine of the 10 karyotyped p53(+) acute myeloid leukemia/myelodysplastic syndrome cases showed complex cytogenetic findings with frequent involvement of chromosome 5 and/or 7. Only four of the 33 karyotyped p53(-) cases showed similar cytogenetic changes. Chromosome 17 involvement was present in four of 13 (31%) cytogenetically assessed p53+ cases, but in none of the p53(-). In univariate analysis, p53 expression in both MDS and AML was significantly associated with shorter survival. The frequent overexpression of p53 in therapy-related myelodysplastic syndromes, therapy-related acute myeloid leukemias and in accelerated phase/blast crisis, chronic granulocytic leukemia and its strong association with complex karyotypes suggests an important role of this gene in the pathogenesis of these leukemic conditions.
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PMID:Frequent p53 overexpression in therapy related myelodysplastic syndromes and acute myeloid leukemias: an immunohistochemical study of bone marrow biopsies. 824 7

Mutations of the p53 tumour suppressor gene on chromosome 17p are a common genetic change in the malignant progression of many cancers. Here we report a case of a 71-year-old man with haematological, cytofluorimetric and cytochemical findings consistent with a 'de novo' M2 acute myeloid leukaemia (AML). A complex karyotype including a whole chromosome 17 and a t(17;?) (p11;?) was present in 8 of 10 metaphases of bone marrow cells. Southern blot analysis of the bone marrow DNA showed a specific loss of p53 gene in the AML cells. As far as we know, this is the first report of a deletion of both p53 alleles in leukaemia. The effect of the loss of p53 on the course of AML is discussed.
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PMID:Total loss of p53 DNA sequences in acute myeloid leukemia. 828 69

In her 8 1/2 years of life, a girl with neurofibromatosis type 1 (NF1) developed four sequential primary malignant neoplasms: Wilms tumor, T-cell acute lymphoblastic leukemia, medulloblastoma and acute myeloid leukemia. The last three tumors were characterized by chromosomal abnormalities non-randomly associated with that particular disease. There was no evidence of germline p53 mutation or of mutation of p53 in the last two tumors. We hypothesize that an unusual mutation of the NF1 gene in this child promoted growth in tissues where the normal or mutated NF-1 gene product is usually silent or growth inhibitory.
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PMID:Sequential development of Wilms tumor, T-cell acute lymphoblastic leukemia, medulloblastoma and myeloid leukemia in a child with type 1 neurofibromatosis: a clinical and cytogenetic case report. 838 72

We screened 23 cases of Philadelphia chromosome (Ph1)-positive acute leukemia (Ph1AL) for loss of a chromosome 17p and mutations in exons 2 to 11 of the p53 gene by single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. Loss of a distal part of chromosome 17p including loss of a whole chromosome 17 emerged in three cases, among which two were Ph1-positive acute lymphoblastic leukemia (Ph1ALL) with point mutations within the highly conserved region of the p53 gene. Another case of Ph1-positive acute myelogenous leukemia (Ph1AML) also exhibited a p53 point mutation in company with loss of normal p53 allele, although showing normal chromosome 17 homologues. We also performed Southern blot hybridization analysis to examine p53 gene rearrangements in 13 cases of Ph1AL. We found a rearrangement in one case of Ph1ALL and a loss of heterozygosity (LOH) at the p53 locus without any rearrangement in another Ph1ALL. Both cases showed no abnormality within the entire coding region by SSCP analysis. Thus, p53 gene alterations were commonly involved in Ph1AL with loss of a 17p (two point mutations in three cases), while rarely in cases with normal chromosome 17s (one point mutation in 20 cases and one rearrangement in 13 cases). Rare p53 gene alterations in Ph1AL may therefore be related to low incidence of loss of a chromosome 17p.
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PMID:p53 gene mutations and loss of a chromosome 17p in Philadelphia chromosome (Ph1)-positive acute leukemia. 841 16

Increased incidence of p53 gene aberrations or chromosome 17p monosomy resulting from an isochromosome 17q [i(17q)] has been observed with transition of chronic myelogenous leukemia (CML) to myeloid blast crisis (BC), and in some patients with poor risk acute myeloid leukemia (AML) progressing from myelodysplastic syndrome (MDS). These data suggested that disease progression may be linked to bi-allelic inactivation of p53. Here, we report on p53 gene analyses of nine patients with CML-BC and AML who showed an i(17q) as characteristic cytogenetic anomaly. Using Southern blots, agarose gel electrophoresis and single-strand conformation polymorphism analyses of PCR products from genomic DNA and cDNA, spanning exons 4 through 9, we did not detect any structural abnormalities of the remaining p53 allele. These findings question the hypothesis that p53 gene alterations are the principal molecular event responsible for progression of CML chronic phase or MDS to i(17q)-positive CML-BC or AML, respectively.
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PMID:Analysis of the p53 gene in patients with isochromosome 17q and Ph1-positive or -negative myeloid leukemia. 850 51

We analysed p53 mutations in 24 patients with myelodysplastic syndrome (MDS) and overt acute myeloid leukaemia after a period of MDS, using polymerase chain reaction-single strand conformation polymorphism analysis. In exons 5 to 8, mobility shifts were detected in five of the 24 patients. Sequence analysis was subsequently performed, and four missense mutations (16.7%) and one silent nucleotide substitution were identified. Patients harbouring mutations were characterized as having advanced disease. Loss of the wild type allele was observed in three of the four patients with missense mutations. No mobility shifts of the N-ras or FMS gene were detected in these four patients. We next analysed the correlation of the p53 mutations with the progression of MDS in three patients. The mutation was accompanied by the progression in two of the three patients. These findings suggest that mutations of the p53 gene are associated with progression in some cases of MDS, while being compatible with stable disease or clonal evolution in others.
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PMID:Mutations of the p53 gene in myelodysplastic syndrome and overt leukemia. 855 5


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