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)

In the 8;21 translocation, the AML1 gene, located at chromosome band 21q22, is translocated to chromosome 8 (q22), where it is fused to the ETO gene and transcribed as a chimeric gene. AML1 is the human homolog of the recently cloned mouse gene pebp2 alpha B, homologous to the DNA binding alpha subunit of the polyoma enhancer factor pebp2. AML1 is also involved in a translocation with chromosome 3 that is seen in patients with therapy-related acute myeloid leukemia and myelodysplastic syndrome and in chronic myelogenous leukemia in blast crisis. We have isolated a fusion cDNA clone from a t(3;21) library derived from a patient with therapy-related myelodysplastic syndrome; this clone contains sequences from AML1 and from EAP, which we have now localized to band 3q26. EAP has previously been characterized as a highly expressed small nuclear protein of 128 residues (EBER 1) associated with Epstein-Barr virus small RNA. The fusion clone contains the DNA binding 5' part of AML1 that is fused to ETO in the t(8;21) and, in addition, at least one other exon. The translocation replaces the last nine codons of AML1 with the last 96 codons of EAP. The fusion does not maintain the correct reading frame of EAP and may not lead to a functional chimeric protein.
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PMID:The 3;21 translocation in myelodysplasia results in a fusion transcript between the AML1 gene and the gene for EAP, a highly conserved protein associated with the Epstein-Barr virus small RNA EBER 1. 839 54

The fusion transcript AML1/ETO was detected in the bone marrow of two t(8;21)-negative acute myelogenous leukemia (AML) patients by means of reverse transcription-polymerase chain reaction. This fusion transcript is identical to the one transcribed from the t(8;21) translocation base, as deduced from (a) the size and restriction pattern of the amplified DNA fragment and (b) the DNA sequence analysis of the fusion junction. We also showed that the ETO gene is highly expressed in these patients, much as it is in the t(8;21)-positive AML. Southern blot analysis showed rearrangement of the AML1 gene in one of the patients. Together, our results demonstrate that there is a masked t(8;21) translocation in AML that is not detectable by cytogenetic analysis but is able to transcribe an AML1/ETO fusion transcript similar to that transcribed in t(8;21)-positive AML-M2 patients.
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PMID:Detection of the AML1/ETO fusion transcript in the t(8;21) masked translocation in acute myelogenous leukemia. 840 10

The AML1 gene on chromosome 21 is disrupted in the (8;21)(q22;q22) translocation associated with acute myelogenous leukemia and encodes a protein with a central 118-amino-acid domain with 69% homology to the Drosophila pair-rule gene, runt. We demonstrate that AML-1 is a DNA-binding protein which specifically interacts with a sequence belonging to the group of enhancer core motifs, TGT/cGGT. Electrophoretic mobility shift analysis of cell extracts identified two AML-1-containing protein-DNA complexes whose electrophoretic mobilities were slower than those of complexes formed with AML-1 produced in vitro. Mixing of in vitro-produced AML-1 with cell extracts prior to gel mobility shift analysis resulted in the formation of higher-order complexes. Deletion mutagenesis of AML-1 revealed that the runt homology domain mediates both sequence-specific DNA binding and protein-protein interactions. The hybrid product, AML-1/ETO, which results from the (8;21) translocation and retains the runt homology domain, both recognizes the AML-1 consensus sequence and interacts with other cellular proteins.
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PMID:Identification of AML-1 and the (8;21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins: the runt homology domain is required for DNA binding and protein-protein interactions. 841 32

The (8;21)(q22;q22) translocation is a frequent karyotypic abnormality seen in approximately 40% of patients with acute myeloid leukemia subtype M2 (AML-M2) and an abnormal karyotype. The translocation interrupts two genes, AML1 on chromosome 21 and ETO on chromosome 8, that are consequently fused in the der(8) chromosome to produce a novel chimeric gene and message. Selected genomic DNA probes from chromosome 21 and from chromosome 8 near the breakpoint junction detect rearrangements in the DNA of about 80% of the patients with the rearrangement at diagnosis and in relapse. We analyzed the DNA of 20 patients with t(8;21) AML by standard Southern blot with probes originating from chromosomes 21 and 8 near the breakpoint junction, and we identified rearranged bands in 17 of the 20 patients at diagnosis and in relapse. We also used the polymerase chain reaction (PCR) with appropriate primers from the AML1 and ETO genes to amplify the cDNAs from a cell line with the t(8;21) and from seven AML patients with the t(8;21). We detected a fused transcript in the cell line and in all of the patients analyzed, including three patients who did not show any rearrangement by Southern blot analysis and one patient in hematologic remission, who later relapsed. Combining the results from Southern blot and PCR analysis, we could detect the t(8;21) in all of the patients tested. These results indicate that, whereas several DNA probes used as genetic markers do detect the t(8;21) in most, but not all Southern blots of patients with AML, PCR amplification with primers from AML1 and ETO can be used as a more sensitive and accurate means for detecting this chromosomal abnormality, and for observing the patients' response to therapy.
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PMID:Detection of DNA rearrangements in the AML1 and ETO loci and of an AML1/ETO fusion mRNA in patients with t(8;21) acute myeloid leukemia. 842 96

The t(8;21) translocation breakpoint, which is observed in acute myeloid leukemia (AML), has recently been cloned and a fusion transcript identified. We have now designed primer sets capable of amplifying the breakpoint junction of the fusion transcript by the reverse transcription-polymerase chain reaction (RT-PCR). Primer set 821U/821D1 amplified a 200-bp DNA fragment, and primer set 821U/821D2 amplified a 1.2-kb DNA fragment in all t(8;21)-positive AML tested. Sequence analysis of the amplified DNA fragments demonstrated that all fusion transcripts were fused at exactly the same site, indicating that this translocation breakpoint occurs within a single intron of the AML1 and ETO genes. Forty-five cycles of RT-PCR were used to detect residual t(8;21)-positive leukemia cells in three patients who had been in complete remission for 1, 3 and 5 years. Minimal residual disease was found in all three samples. Northern blot analysis demonstrated that two fusion transcripts of 7 and 10 kb were expressed in the t(8;21)-positive AML and that the ETO gene is not normally expressed in the hematopoietic system. Expression of a normal 5.5-kb ETO mRNA was found in the lung. From these results we concluded that expression of the ETO gene in t(8;21)-positive AML was activated as a result of the translocation.
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PMID:Expression of AML1-ETO fusion transcripts and detection of minimal residual disease in t(8;21)-positive acute myeloid leukemia. 845 49

A nonrandom translocation between chromosomes 3 and 21, t(3;21)(q26.2;q22) has been detected in patients with a myelodysplastic syndrome or acute myeloid leukemia after treatment (t-MDS/t-AML) for a primary malignant disease and in chronic myelogenous leukemia in blast crisis (CML-BC). In these patients, the breakpoint on chromosome 21 is at band 21q22. This band is also involved in the t(8;21)(q22;q22) detected in 40% of the patients with acute myeloid leukemia subtype M2 (AML-M2) de novo who have an abnormal karyotype. In the t(8;21), the AML1 gene is the site of the breakpoint on chromosome 21. The AML1 gene is transcribed from telomere to centromere, and in the t(8;21) the 5' part of AML1 is fused to the ETO gene on chromosome 8 to produce the chimeric AML1/ETO on the der(8) chromosome. We found that AML1 is also rearranged in two t-AML patients and in one CML-BC patient with the t(3;21), but the breakpoints are approximately 40 to 60 kb downstream to those of AML-M2 patients. This region contains at least one additional exon of AML1, as determined by using an AML1 cDNA as a probe in Southern blot analysis. The t(3;21) breakpoints for the remaining patients could not be determined because, by fluorescence in situ hybridization analysis, the breaks are outside of the region covered by the available probes.
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PMID:Involvement of the AML1 gene in the t(3;21) in therapy-related leukemia and in chronic myeloid leukemia in blast crisis. 849 Jan 81

The 8;21 translocation is one of the most common chromosomal translocations in acute myelogenous leukemia (AML), accounting for 40% of pediatric AML with French-American-British (FAB)-M2 morphology. The chromosomal breakpoints have recently been identified at the molecular level and shown to involve the AML1 gene on chromosome 21 and the ETO gene on chromosome 8. Translocation results in the consistent fusion of these genes on the der(8) chromosome, resulting in the production of a novel chimeric gene and message. Using oligonucleotide primers derived from the AML1 and ETO cDNAs, we were able to amplify a specific fusion transcript from 26 of 26 patients with t(8;21) by a reverse transcriptase polymerase chain reaction (PCR) approach. DNA fragments of identical size were generated from each case including two with complex translocations. Studies on the sensitivity and specificity of this approach show that PCR analysis can be used as a rapid, accurate, and sensitive means for detecting this chromosomal abnormality, and for following the patients' response to therapy.
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PMID:An AML1/ETO fusion transcript is consistently detected by RNA-based polymerase chain reaction in acute myelogenous leukemia containing the (8;21)(q22;q22) translocation. 849 24

The t(8;21) translocation, commonly found in acute myelogenous leukemia (AML), generates a fusion protein containing N-terminal AML1 and C-terminal ETO amino acids. The human AML1 gene encodes several related proteins that specifically bind to the sequence TGT/cGGT, located in the promoter regions of a variety of hematopoietic growth factor genes. To examine the abilities of the AML1B protein (which contains 479 amino acids), a shorter AML1A isoform (which contains amino acids 1-250), and the AML1/ETO fusion protein (which contains AML1A amino acids 1-177) to stimulate transcription from the GM-CSF promoter, we performed co-transfection experiments in T cells using a human GM-CSF promoter-CAT reporter gene plasmid and expression vectors that contain the cDNAs for one of the above proteins. Our data demonstrate that AML1B, but not AML1A or AML1/ETO transactivates the GM-CSF promoter, requiring the TGTGGT sequence contained between base pairs -68 and -53. Furthermore, we show that AML1/ETO, but not AML1A, inhibits the ability of AML1B to stimulate CAT expression. Electrophoretic mobility shift assays demonstrated the specific binding of AML1 proteins to the GM-CSF promoter TGTGGT sequence, which does not require GM-CSF sequences immediately upstream of this binding site. Our data support a role for AML1B as a transcriptional activator and establish that the AML1/ETO fusion protein can act as a dominant negative protein on the human GM-CSF promoter. Although AML1/ETO does not stimulate the transcription of GM-CSF, it may function by inhibiting the normal activity of AML1B in AML cells with the t(8;21) translocation.
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PMID:The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML1B. 854 24

Acute leukemia (AL) is a relatively uncommon, but dreaded, complication occurring with increased frequency in individuals with Down syndrome (DS). This selective update includes aspects of AL in DS in which a change or advancement in our understanding of this disease has occurred. Despite previous reports describing a worse outcome for these individuals, more recent studies have suggested an improved response to current treatment strategies (including high-dose AraC) equaling, or even surpassing, the survival of non-DS individuals with AL. An increased toxicity to methotrexate in DS patients has also been recognized. While the leukemia of DS infants has been described as megakaryoblastic, the spectrum of in vitro differentiation is much broader including (in addition to megakaryocytic colonies) various myeloid, macrophage, and even erythroid colonies. Although the cause(s) of DS-AL remains unknown, potential candidate genes include those encoded on chromosome 21 that play a role in other defined leukemias in non-DS individuals. The AML1/PEBP2alpha gene maps to the DS critical region and is characteristically associated with two leukemia-associated chromosomal translocations: 1) the 8;21 translocation involving an AML1/ETO fusion transcript commonly seen in acute myelogenous leukemia (AML) and; 2) a 3;21 translocation identified in certain chemotherapy-related myelodysplasias/leukemias and occasionally in the blast crisis of chronic myelogenous leukemia cells. Similarly, the ETS-related gene, ERG, involved in the AML 16;21 maps to the q22 region of chromosome 21. Lastly, a familial platelet disorder with a propensity to develop myeloid leukemia has been linked to 21q22.1-22.2 and conceivably might involve AML1, ERG or yet another gene.
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PMID:Down syndrome and leukemia, an update. 854 49

In a study of 23 patients with t(8;21)-associated acute myeloid leukaemia the AML1-MTG8 fusion transcript was present in the majority of serial samples obtained from 17 patients followed for up to 34 months after diagnosis, but was absent in samples from all six patients who had been in continuous complete remission for 61 months after allogeneic bone marrow transplantation (BMT), or for 52, 53, 123, 182 and 198 months, respectively, after courses of intensive chemotherapy. Previous studies showed that the AML1-MTG8 fusion transcript was present in most patients with this type of translocation in long-term remission. Our results indicate that blood cells of patients with t(8;21) in remission of over 10 years may not show the AML1-MTG8 fusion transcript, and that those of patients who have undergone allogeneic BMT or intensive chemotherapy may become fusion transcript-negative much earlier. Our study suggests that leukaemic cells with the AML1-MTG8 fusion transcript may survive for some time after courses of chemotherapy or BMT, but that they may eventually be eradicated by immunologic and other antileukaemic mechanisms.
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PMID:Disappearance of AML1-MTG8(ETO) fusion transcript in acute myeloid leukaemia patients with t(8;21) in long-term remission. 854 35


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