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

We have developed a restriction map of the chromosome 21 breakpoint region involved in t(8;21)(q22;q22.3) acute myelogenous leukemia (AML) and have isolated a genomic junction clone containing chromosome 8 and 21 material. Using probes from these regions, rearrangements have been identified in each of nine cases of t(8;21) AML examined. In addition, we have isolated cDNA clones from a t(8;21) AML cDNA library that contain fused sequences from chromosome 8 and 21. The chromosome 8 component, referred to as ETO (for eight twenty-one), is encoded over a large genomic region, as suggested by the analysis of corresponding yeast artificial chromosomes (YACs). The DNA sequence of the chromosome 21 portion of the fusion transcript is derived from the normal AML1 gene. A striking similarity (67% identity over 387 bp, with a corresponding 69% amino acid identity) was detected between AML1 and the Drosophila segmentation gene, runt. The critical consequence of the translocation is the juxtaposition of 5' sequences of AML1 to 3' sequences of ETO, oriented telomere to centromere on the der(8) chromosome.
 ...
PMID:Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. 139 46

The AML-1/ETO fusion protein is created by the (8;21) translocation, the second most frequent chromosomal abnormality associated with acute myeloid leukemia. In the fusion protein the AML-1 runt homology domain, which is responsible for DNA binding and CBF beta interaction, is linked to ETO, a gene of unknown function. The primary sequences of the runt homology domain indicates no known DNA binding motifs, but is predicted to contain six beta-strands, two alpha-helices and a nucleotide binding motif. Mutagenesis of AML-1/ETO was performed to delimit the functional domains of the chimeric protein. Most mutations in the runt homology domain that resulted in reduced CBF beta binding also inhibited DNA binding, indicating that the DNA and CBF beta binding sequences are tightly linked. However, these activities were separated by a point mutation of residue 144, within the putative ATP binding motif, which nearly eliminated DNA binding, but did not affect CBF beta binding. Random mutagenesis identified the hydrophobic face of the amphipathic fifth beta-strand, adjacent to the putative ATP binding motif, as critical for both DNA and CBF beta binding. C-terminal deletion mutants of AML-1/ETO indicated that ETO sequences are essential for interference with AML-1B-mediated transcriptional activation, and that residue 540 defines the C-terminal boundary of a potential repression domain. Thus, these mutational analyses define the regions of AML-1/ETO which regulate its function and that may be important in promoting leukemia.
 ...
PMID:Functional domains of the t(8;21) fusion protein, AML-1/ETO. 747 4

The AML1/MTG8 fusion gene is thought to have a critical role in the leukemogenesis of AML with t(8;21)(q22;q22). To specifically inhibit the proliferation of leukemic cells having the AML1/MTG8 fusion gene, we constructed two hammerhead ribozymes against AML1/MTG8. Two cleavage sites were targeted as follows: site 1 for ribozyme 1(Rz1), a CUC located 3 bases upstream from the fusion site; site 2 for ribozyme 2(Rz2), an AUC located 3 bases downstream from the fusion site. In a cell-free system, Rz1 and Rz2 specifically cleaved AML1/MTG8 substrate, dependent on the concentration of ribozymes. When these ribozymes were transfected to Kasumi-1 cells, an AML cell line with AML1/MTG8, they were able to inhibit the cell growth. These data suggest that Rz1 and Rz2 may be applied as a new therapeutic agent in the treatment of AML with t(8;21).
 ...
PMID:Ribozymes cleave the AML1/MTG8 fusion transcript and inhibit proliferation of leukemic cells with t(8;21). 748 74

1. The (8;21) translocation, which is consistently associated with a subgroup of acute myeloid leukaemia, involves two loci: runt on chromosome 21 and MTG8 on chromosome 8. 2. Breakpoints in runt fall within a single intron that is located immediately downstream of a phylogenetically conserved DNA-binding domain (the 'runt box'). 3. We now show that most breakpoints on chromosome 8 fall within a region between two alternative 5' MTG8 exons. Thus, we predict that chimaeric genes on both the derivative(8) and the derivative(21) chromosomes have the potential to be transcriptionally active.
 ...
PMID:t(8;21) breakpoints are clustered between alternatively spliced exons of MTG8. 749 14

AML with eosinophilia belongs to the morphologic cytogenetic entity M1/M2 t(8;21) with the involvement of the genes AML1/ETO. These eosinophils differ only slightly from normal eosinophils with one rare exception i.e. Auer rods in eosinophils which has only been found on peroxidase staining: This subtype belongs to the good prognosis group of AML. AML with inv(16) (mostly M4Eo) per se is a morphologic-cytogenetic entity with inv(16),--rarely t(16;16), and the genes MYL 11/CBF beta involved. The eosinophils show special abnormalities. AML with inv(16) also belongs to the good prognosis group of AML.
 ...
PMID:AML M1 and M2 with eosinophilia and AML M4Eo: diagnostic and clinical aspects. 749 57

The nonrandom chromosomal translocation t(8;21)(q22;q22) can be found frequently in acute myelogenous leukemia with maturation (AML-M2). The breakpoint of this translocation has been cloned and characterized, and fusion transcript AML1/ETO has been identified. Reverse transcription polymerase chain reaction (RT-PCR) can be used to amplify the breakpoint site of AML1/ETO in t(8;21)-positive AML-M2 patients. The chimeric transcript can be detected in all 16 (100%) t(8;21)-positive AML-M2 patients. In all samples, the size of the amplified DNA fragments and pattern of restriction digest were identical, indicating that the t(8;21) translocation breakpoint occurs within a single intron of the AML1 and ETO genes. Interestingly, this fusion transcript was also detected in one of 13 AML-M2 patients without the t(8;21) translocation, indicating that a masked translocation involving chromosomes 8 and 21, exists in AML. Minimal residual disease was detected by semi-nested RT-PCR in all four patients tested, who had been in complete remission for 12, 15, 34, and 52 months, respectively. These results indicate that RT-PCR amplification of the AML1/ETO fusion transcript is a powerful tool for diagnosing and monitoring minimal residual disease in AML-M2 patients.
 ...
PMID:Detection of AML1/ETO fusion transcript as a tool for diagnosing t(8;21) positive acute myelogenous leukemia. 750 93

Rearrangements of the AML-1 gene on chromosome 21 as well as transcriptional expression of AML-1-ETO fusion gene were studied in 35 leukemic patients with t(8;21)(q22;q22). A panel of probes generated from the AML-1 gene regions flanking the breakpoint on chromosome 21 allowed us to detect the rearrangement in 24 out of 29 patients. A specific nested reverse transcriptase/polymerase chain reaction (RT/PCR) was developed to detect the t(8;21), either at diagnosis or as minimal residual disease. PCR amplification products were obtained in ten out of 11 patients investigated, and the sensitivity of the reaction was estimated to be between 1 x 10(4) and 1 x 10(-5) cell. An AML-1 rearrangement was also detected in one patient with 8q- and only one chromosome 21, but without 21q+. This indicated that the molecular rearrangement of the der(8) chromosome is more important than the reciprocal one in the malignant process.
 ...
PMID:AML-1 gene rearrangement and AML-1-ETO gene expression as molecular markers of acute myeloblastic leukemia with t(8;21). 751 41

The chromosomal translocation t(8;21)(q22;q22) in acute myeloid leukemia (AML) can be detected by a reverse transcription-polymerase chain reaction (RT-PCR) for the chimeric AML1/ETO transcript. We have evaluated the clinical relevance of this method for monitoring and detection of minimal residual disease (MRD) in seven patients who reached a complete hematological remission (CHR) after chemotherapy or autologous bone marrow transplantation (ABMT). Peripheral blood (PB) samples of five patients in first continuous complete remission (CCR) were still PCR-positive at a frequency of 1 in 10(5) cells after 7, 8, 8, 10 or 66 months. Chemotherapy led to a reduction from first- to second-step PCR-positivity in three serially monitored patients. AML1/ETO mRNA was also detected in the PB of two patients in CCR, 10 or 12 months after ABMT. PB and bone marrow (BM) showed identical results in all samples tested simultaneously. AML1/ETO fusion transcripts were neither found in the PB and BM of a healthy individual, nor in the PB of a patient after allogeneic BMT for cytogenetically proven t(8;21)-leukemia. Our results indicate the presence of cells carrying the AML1/ETO rearrangement in the PB and BM of all patients in CHR after chemotherapy or ABMT for t(8;21)-positive AML. While this finding raises interesting questions about the biology of acute leukemia, it limits the value of the AML/ETO RT-PCR for the prediction of impending relapse.
 ...
PMID:AML1/ETO fusion mRNA can be detected in remission blood samples of all patients with t(8;21) acute myeloid leukemia after chemotherapy or autologous bone marrow transplantation. 751 42

The 8;21 chromosomal translocation involves the AML1 gene on chromosome 21 and the ETO gene on chromosome 8 and results in the transcription of a chimeric message. This translocation is most often associated with acute myelogenous leukemia with maturation (AML-M2). The leukemic cells of patients carrying t(8;21) often exhibit several characteristic morphologic features. We identified four cases in which the morphology led us to suspect a t(8;21), but in which this translocation was not observed by cytogenetic analysis. In two of the four cases, an AML1/ETO chimeric fragment was detected by reverse transcription and polymerase chain reaction (RT-PCR), and its sequence was found to be identical to that from patients with a cytogenetically proved t(8;21). Marrow specimens of the four patients lacking the t(8;21) cytogenetically were reviewed retrospectively with regard to seven morphologic features commonly reported to be associated with this translocation, and the results were compared to 13 morphologic controls with the t(8;21). Although none of the 13 controls had all of the characteristic morphologic features, all had at least six, as did the two t(8;21)-negative but RT-PCR-positive patients. The two patients who lacked the t(8;21) and who were RT-PCR-negative showed only three and four of these morphologic features, respectively. Both of the RT-PCR-positive patients had deletions of the long arm of chromosome 9, a common change associated with a t(8;21), supporting our assessment of these patients as having a cytogenetically undetected t(8;21).
 ...
PMID:Correlation between cell morphology and expression of the AML1/ETO chimeric transcript in patients with acute myeloid leukemia without the t(8;21). 752 91

Patients with acute myeloid leukaemia with maturation (AML-M2) that carried the t(8;21) were tested for the presence of chimeric AML1/ETO mRNA. After RT-PCR, an expected band of 208 bp was observed on gel, as well as some slower migrating bands. The base composition of one of the additional products was determined and was found to contain a new 68-bp ETO sequence present at the fusion of AML1 and ETO genes. The derived protein sequence results in a truncated AML1 gene still containing the putative DNA binding domain. Molecular diversity in the AML1-ETO transcripts will have consequences for the detection of minimal residual disease and antisense studies.
 ...
PMID:Molecular diversity in AML1/ETO fusion transcripts in patients with t(8;21) positive acute myeloid leukaemia. 752 1


1 2 3 4 5 6 7 8 9 10 Next >>