UMLS:C0023467 - FACTA Search

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Query: UMLS:C0023467 (acute myeloid leukemia)
35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AML1, a gene encoding a protein of the PEBP2/CBF family of transcription factors is disrupted by translocations associated with human leukemia. In the t(8;21) acute myelogenous leukemia (AML), AML1 was found fused to a gene on chromosome 8 that we designated CDR (also known as ETO and MTG8). Immunoprecipitation experiments followed by immunoblotting using a combination of antibodies against different epitopes of one of the predicted chimeric proteins encoded by a fully characterized fusion transcript enabled us to visualize a chimeric protein in the t(8;21) Kasumi-1 cell line. The estimated size of this protein is 64 kDa. Immunoblotting of leukemic blasts containing the t(8;21) detected a protein of the same size. Immunofluorescence experiments indicate that the chimeric protein is localized in the nucleus. A normal AML1 protein of 27 kDa was also detected in t(8;21) Kasumi-1 cells. It remains to be established by which mechanism the mutant AML1 isoform may contribute to the leukemogenesis process of t(8;21)-positive acute myeloid leukemia.
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PMID:Detection and subcellular localization of an AML1 chimeric protein in the t(8;21) positive acute myeloid leukemia. 857 Feb 22

The human CBFA2T1 (also known as MTG8) gene, on chromosome 8, has been identified through its involvement in the t(8;21) chromosomal translocation, frequently found in acute myeloid leukemia. We report here the isolation and characterization of the mouse homologue of the CBFA2T1 gene, Cbfa2t1h. Nucleotide sequence analysis of Cbfa2t1h cDNA clones revealed an open reading frame encoding a protein of 577 amino acids with an extremely high degree of amino acid identity (99.3%) to the human protein. The nucleotide sequence is also highly conserved between mouse and human in the 5'- and 3'-untranslated regions (87.0, 92.0, and 93.7% identities for 5'-untranslated, coding, 3'-untranslated regions, respectively). The 3'-untranslated region of Cbfa2t1h contains a (CA)n dinucleotide repeat, and the polymerase chain reaction amplification of the (CA)n repeat region revealed fragment length polymorphism among mouse strains. Using this polymorphism, we have mapped Cbfa2t1h to mouse chromosome 4 close to the centromere using SMXA recombinant inbred strains and 106 intersubspecific backcross progenies of the (DBA/2 x Mae) x Mae cross. The chromosomal location was also confirmed by fluorescence in situ hybridization.
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PMID:Cloning and gene mapping of the mouse homologue of the CBFA2T1 gene associated with human acute myeloid leukemia. 857 70

Several recurring chromosomal translocations involve the AML1 gene at 21q22 in myeloid leukemias resulting in fusion mRNAs and chimeric proteins between AML1 and a gene on the partner chromosome. AML1 corresponds to CBFA2, one of the DNA-binding subunits of the enhancer core binding factor CBF. Other CBF DNA-binding subunits are CBFA1 and CBFA3, also known as AML3 and AML2. AML1, AML2 and AML3 are each characterized by a conserved domain at the amino end, the runt domain, that is necessary for DNA-binding and protein dimerization, and by a transactivation domain at the carboxyl end. AML1 was first identified as the gene located at the breakpoint junction of the 8;21 translocation associated with acute myeloid leukemia. The t(8;21)(q22;q22) interrupts AML1 after the runt homology domain, and fuses the 5' part of AML1 to almost all of ETO, the partner gene on chromosome 8. AML1 is an activator of several myeloid promoters; however, the chimeric AML1/ETO is a strong repressor of some AML1-dependent promoters. AML1 is also involved in the t(3;21)(q26;q22), that occurs in myeloid leukemias primarily following treatment with topoisomerase II inhibitors. We have studied five patients with a 3;21 translocation. In all cases, AML1 is interrupted after the runt domain, and is translocated to chromosome band 3q26. As a result of the t(3;21), AML1 is consistently fused to two separate genes located at 3q26. The two genes are EAP, which codes for the abundant ribosomal protein L22, and MDS1, which encodes a small polypeptide of unknown function. In one of our patients, a third gene EVI1 is also involved. EAP is the closest to the breakpoint junction with AML1, and EVI1 is the furthest away. The fusion of EAP to AML1 is not in frame, and leads to a protein that is terminated shortly after the fusion junction by introduction of a stop codon. The fusion of AML1 to MDS1 is in frame, and adds 127 codons to the interrupted AML1. Thus, in the five cases that we studied, the 3;21 translocation results in expression of two coexisting chimeric mRNAs which contain the identical runt domain at the 5' region, but differ in the 3' region. In addition, the chimeric transcript AML1/MDS1/EVI1 has also been detected in cells from one patient with the 3;21 translocation as well as in one of our patients. Several genes necessary for myeloid lineage differentiation contain the target sequence for AML1 in their regulatory regions. One of them is the CSF1R gene. We have compared the normal AML1 to AML1/MDS1, AML1/EAP and AML1/MDS1/EVI1 as transcriptional regulators of the CSF1R promoter. Our results indicate that AML1 can activate the promoter, and that the chimeric proteins compete with the normal AML1 and repress expression from the CSF1R promoter. AML1/MDS1 and AML1/EAP affect cell growth and phenotype when expressed in rat fibroblasts. However, the pattern of tumor growth of cells expressing the different chimeric genes in nude mice is different. We show that when either fusion gene is expressed, the cells lose contact inhibition and form foci over the monolayer. In addition, cells expressing AML1/MDS1 grow larger tumors in nude mice, whereas cells expressing only AML1/EAP do not form tumors, and cells expressing both chimeric genes induce tumors of intermediate size. Thus, although both chimeric genes have similar effects in transactivation assays of the CSF1R promoter, they affect cell growth differently in culture and have opposite effects as tumor promoters in vivo. Because of the results obtained with cells expressing one or both genes, we conclude that MDS1 seems to have tumorigenic properties, but that AML1/EAP seems to repress the oncogenic property of AML1/MDS1.
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PMID:Rearrangement of the AML1/CBFA2 gene in myeloid leukemia with the 3;21 translocation: expression of co-existing multiple chimeric genes with similar functions as transcriptional repressors, but with opposite tumorigenic properties. 858 55

For therapeutic purposes, two chimeric DNA/RNA hammerhead ribozymes were synthesized to cleave AML1/MTG8, the t(8;21)-associated fusion mRNA of acute myeloid leukemia. One ribozyme, A/MRZ-1, recognizes the area adjacent to the fusion point between AML1 and MTG8, and cleaves six bases downstream from this point. The other, MRZ-1, recognizes the MTG8 sequence. Both ribozymes cleaved synthetic chimeric DNA/RNA substrates at theoretical sites. Neither cleaved AML1 RNA. A/MRZ-1 cleaved only AML1/MTG8 RNA, and MRZ-1 cleaved both AML1/MTG8 and MTG8 RNAs. The two ribozymes showed growth inhibition of an acute myeloid leukemia cell line carrying t(8;21), SKNO-1 cells. The same extent of growth inhibition was attained by antisense oligonucleotides against AML1/MTG8 RNA. The results suggest that the ribozyme has the potential to be developed as a useful agent for gene therapy, in particular for leukemia with t(8;21).
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PMID:Designing of chimeric DNA/RNA hammerhead ribozymes to be targeted against AML1/MTG8 mRNA. 860 80

The t(8;21) identifies a subgroup of acute myeloid leukaemia (AML) with a relatively good prognosis which may merit different treatment. It is associated predominantly, but not exclusively, with AML M2, and corresponds to rearrangements involving the AML1 and ETO genes. AML1-ETO positive, t(8;21) negative cases are well recognized but their incidence is unknown. In order to determine optimal prospective AML1-ETO RT-PCR screening strategies, we analysed 64 unselected AML M1 and M2 cases and correlated the results with other biological parameters. Molecular screening increased the overall detection rate from 8% to 14%. AML1-ETO was found in 3% (1/32) of AML M1 and 25% (8/32) of M2, including three patients without a classic (8;21) but with chromosome 8 abnormalities. It was more common in younger patients. Correlation with morphology enabled development of a scoring system which detected all nine AML1-ETO-positive cases with a false positive rate of 7% (4/55). Although certain AML1-ETO-positive cases demonstrated characteristic immunological features (CD19 and CD34 expression, CD33 negativity), each of these markers was insufficiently specific to permit prediction in an individual case. We conclude that initial routine prospective molecular screening for AML1-ETO in all AMLs, combined with standardized morphological and immunological analysis, is desirable in order to produce improved prognostic stratification and to determine whether screening can ultimately be restricted to appropriate subgroups.
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PMID:Molecular detection of t(8;21)/AML1-ETO in AML M1/M2: correlation with cytogenetics, morphology and immunophenotype. 861 78

The leukemia-specific AML1/ETO fusion gene has been shown to be detected by reverse transcriptase polymerase chain reaction (RT-PCR) analysis in patients with t(8;21) acute myelogenous leukemia (AML) in long-term remission. In the present study, the AML1/ETO mRNA could be detected by RT-PCR in bone marrow (BM) and/or peripheral blood (PB) samples from all 18 patients who had been maintaining complete remission for 12 to 150 months (median, 45 months) following chemotherapy or PB stem cell transplantation (PBSCT), whereas it could not be detected in four patients who had been maintaining remission for more than 30 months following allogeneic BM transplantation (BMT). We surveyed the expression of AML1/ETO mRNA in clonogenic progenitors from BM in these cases. Notably, 51 of 2,469 colonies from clonogenic progenitors (2.1%) expressed the AML1/ETO mRNA in 18 cases who were RT-PCR+ in BM and/or PB samples. Expression was observed in various clonogenic progenitors, including granulocyte-macrophage colonies, mixed colonies, erythroid colonies, and megakaryocyte colonies. Furthermore, we analyzed the clonality of these progenitors by X-chromosome inactivation patterns of the phosphoglycerate kinase (PGK) gene in four female patients. The AML1/ETO mRNA+ progenitors showed the PGK allele identical to that detected in the leukemic blasts from the time of initial diagnosis. Normal constitutive hematopoiesis was sustained by polyclonal BM reconstitution in these patients. Accordingly, these committed progenitor cells that express AML1/ETO mRNA during remission likely have arisen from common t(8;21)+ pluripotent progenitor cells with at least trilineage differentiation potential. These data strongly suggest that the origin of the clonogenic leukemic progenitors of t(8;21) AML may be multipotent hematopoietic progenitors that acquired the t(8;21) chromosomal abnormality.
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PMID:Persistence of multipotent progenitors expressing AML1/ETO transcripts in long-term remission patients with t(8;21) acute myelogenous leukemia. 863 50

The (8;21) chromosomal translocation occurs in 20% of adult patients with AML M2. This translocation interrupts two genes, AML1 on chromosome 21q and MTG8 (ETO) on 8q to form a chimeric gene AML1/MTG8 on the der(8) chromosome. Recent reports have shown the presence of diverse forms of transcript for this chimeric gene. Three alternative out-of-frame transcripts have been previously demonstrated (types II, III, IV) all of which have a stop codon 3' of the runt box encoding a truncated runt polypeptide. We have characterized a novel transcript (V) which is in-frame and has a stop codon 3' to the runt box. We have examined transcript diversity in 10 AML patients with t(8;21) in remission of their disease following chemotherapy or bone marrow transplantation. Specific transcripts detected at presentation in six patients were similarly expressed during remission and at relapse in two patients; thus expression of transcript diversity was unaffected by the disease phase. Alternative transcripts were unhelpful as a marker of remission quality or predictor of relapse. The significance of these diverse transcripts in leukemogenesis remains unknown.
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PMID:Expression of diverse AML1/MTG8 transcripts is a consistent feature in acute myeloid leukemia with t(8;21) irrespective of disease phase. 868 93

AML-1B is targeted directly and indirectly in multiple chromosomal translocations in myeloid and B-cells. The AML-1/ETO and TEL/AML-1 fusion proteins, created by the t(8;21) and t(12;21) respectively, disrupt AML-1B-dependent transcription. Recently, two human members of the runt homology domain family of transcription factors have been identified, AML-2 and AML-3, which also regulate transcription through enhancer core motifs. If multiple factors regulate transcription through the same site, a dominant interfering protein may be required to promote leukemogenesis, rather than the inactivation of both AML1 alleles. To determine which AML family proteins are active in hematopoietic cells, we developed antisera specific to each family member for use in gel mobility shift assays. We have found that AML-1B is the major DNA binding activity in T-cell lines, while both AML-1B and AML-2 are expressed in myeloid and B-cell lines. AML-1B represents most of the active protein in the mouse thymus, whereas AML-1 and AML-2 are equally expressed in the mouse spleen. AML-3 is expressed at very low levels in a single myeloid cell line, 32D.3, and is the only core binding activity present in Buffalo rat liver cells. We demonstrate that AML-2-dependent transactivation mediated by enhancer core motifs is inhibited by the AML-1/ETO and TEL/AML-1 fusion proteins. This indicates that the t(8;21) and t(12;21) fusion proteins inhibit transcriptional activation by the AML-1 transcription factor family, and in so doing contributes to leukemogenesis.
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PMID:AML-2 is a potential target for transcriptional regulation by the t(8;21) and t(12;21) fusion proteins in acute leukemia. 871 Mar 69

We present a case of a 59-year-old Japanese man with therapy-related acute myeloblastic leukemia (AML) after the chemotherapy for non-Hodgkin's lymphoma (NHL). Accumulated doses of cyclophosphamide, procarbazine, doxorubicin, mitoxantrone, and etoposide were 18,300 mg, 3000 mg, 580 mg, 100 mg, and 4150 mg, respectively, which had been administered for the treatment of NHL. Myeloblasts in the peripheral blood increased 43 months after the onset of NHL. He was diagnosed as having AML (M2; FAB classification). The karyotype of the bone marrow cells in the present case contained the following abnormalities: t(2;21)(q21;q22), t(8;21)(q22;q22), and add(13)(q34). In the present case, 645 base pairs of chimeric mRNA were detected by reverse transcription-polymerase chain reaction, indicating the presence of AML1/MTG8 rearrangement. Translocation (2;21)(q21;q22) has not been described previously to our knowledge. It is interesting that the breakpoint of 21q22 existed both in t(2;21) and t(8;21). The disrupted AML1 gene resulting from two 21q22 rearrangements may be involved in the pathogenesis of AML in the present case. The clinical importance of therapy-related AML having the 21q22 rearrangement remains to be examined.
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PMID:Therapy-related leukemia with a novel 21q22 rearrangement. 878 Jul 46

To study acute myelogenous leukemia 1 (AML1) transcription factor, ETO protein, and t(8;21) AML chimeric AML1/ ETO protein in normal hematopoiesis and in leukemia, we raised rabbit antisera to a bacterially expressed polypeptide containing amino acid residues 1 to 220 of ETO and to synthetic peptides extending from residues 528 to 548 of ETO and 32 to 50 of AML1. The latter was selected to have little chance of cross-reactivity with other members of the PEBP2 alpha family. With affinity-purified reagents, we observed immunofluorescent staining for both AML1 and ETO in the nucleus of HEL, K562, and Kasumi-1 leukemic cell lines, the last from a t(8;21) AML. Biochemical analysis confirmed specificity of the antibodies and the nuclear localization of the antigens, the latter being exclusive for AML1 and primary for ETO. Immunoprecipitations of metabolically labeled 32P-proteins from Kasumi-1 cells show that AML1 and ETO are phosphorylated on serine and threonine. Investigations with normal bone marrow reveal AML1 and ETO are coexpressed in megakaryocytes and that each is expressed in a portion of the approximately 10-microns-diameter cells residing there. Using a CD34+ enriched population mobilized to peripheral blood, we found AML1 and, unexpectedly, ETO present in these cells. Because of this, we conclude that the expression of ETO in hematopoietic cells is not by itself leukemogenic. Also, because ETO would not be exclusively expressed as part of chimeric AML1/ETO in leukemic patients, its presence cannot be used to monitor t(8;21) AML residual disease.
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PMID:ETO and AML1 phosphoproteins are expressed in CD34+ hematopoietic progenitors: implications for t(8;21) leukemogenesis and monitoring residual disease. 878 39

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