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)

The Drosophila runt locus controls early events in embryogenesis. A human homologue (CBFA2) was originally identified because of its involvement in the t(8;21) associated with a subtype of acute myeloid leukaemia. The phylogenetically conserved region (runt box) was reported to correspond to a DNA binding domain. In order to investigate whether runt also plays a role in mammalian development, we have conducted a preliminary survey of its expression in the mouse embryo. Expression in embryonic tissues was detected starting from day 9.2 post coitum. From day 10.5 post coitum, highest levels are found in the neural tube, sensory ganglia, specialised sensory epithelial structures (olfactory and gustatory mucosa, follicles of the vibrissae), all chondrogenic centres (both of neural crest and of mesodermal origin), and the genital system (the gonad, the paramesonephros, and the genital tubercle). Unambiguous expression in the haemopoietic system could be established for the thymus. The data suggest a pleiotropic role for mammalian runt in embryogenesis.
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PMID:Expression of runt in the mouse embryo. 764 75

We previously isolated the AML1 gene, which is rearranged by the t(8;21) translocation in acute myeloid leukemia. The AML1 gene is highly homologous to the Drosophila segmentation gene runt and the mouse transcription factor PEBP2 alpha subunit gene. This region of homology, called the Runt domain, is responsible for DNA-binding and protein--protein interaction. In this study, we isolated and characterized various forms of AML1 cDNAs which reflect a complex pattern of mRNA species. Analysis of these cDNAs has led to the identification of two distinct AML1 proteins, designated AML1b (453 amino acids) and AML1c (480 amino acids), which differ markedly from the previously reported AML1a (250 amino acids) with regard to their C-terminal regions, although all three contain the Runt domain. The large C-terminal region common to AML1b and AML1c is suggested to be a transcriptional activation domain. AML1c differs from AML1b by only 32 amino acids in the N-terminal. Characterization of the genomic structure revealed that the AML1 gene consists of nine exons and spans > 150 kb of genomic DNA. Northern blot analysis demonstrated the presence of six major transcripts, encoding AML1b or AML1c, which can all be explained by the existence of two promoters, alternative splicing and differential usage of three polyadenylation sites. A minor transcript encoding AML1a which results from alternative splicing of a separate exon can be detected only by reverse transcription-polymerase chain reaction amplification. The distinct proteins encoded by the AML1 gene may have different functions, which could contribute to regulating cell growth and/or differentiation through transcriptional regulation of a specific subset of target genes.
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PMID:Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia. 765 38

The very rapid development of techniques based on use of the polymerase chain reaction (PCR) for characterizing molecular lesions in leukaemia and lymphoma mow offers the opportunity for monitoring residual disease at a sensitivity of one malignant cell in 10(5) or 10(6) normal cells. Maximal specificity is achieved when the DNA sequences amplified are truly leukaemia-specific (i.e. BCR/ABL in CML, PML/RAR-alfa in APL, AML1/ETO in t(8; 21) AML and CBFB/MYH1 in inv(16) AML). A good level of sensitivity may also be achieved by using immunoglobin heavy chain (IGH) and T-cell receptor (TCR) gene rearrangements if a clonospecific probe can be generated. For clinical purposes the crucial issues are the following: can PCR techniques be used for confirmation of diagnosis and evaluation of extent of disease? Can PCR data obtained be developed to quantitate the PCR product and thereby increase its predictive value? These and other issues are still a matter of debate and several studies are presently in progress to address these points.
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PMID:Minimal residual disease detection in human leukemias: biologic and clinical significance. 765 31

The translocation between chromosomes 8 and 21, t(8;21)(q22;q22), is the most frequent abnormality seen in approximately 46% of patients with acute myeloid leukemia with French-America-British (FAB)-M2 morphology and an aneuploid karyotype. The breakpoints in this translocation have been characterized at the molecular level, and the genes involved are AML1 on chromosome 21 and ETO (eight twenty one) on chromosome 8. AML1 has homology to the alpha subunit of the murine polyoma enhancer binding protein, pebp2, and to the segmentation gene, runt, of Drosophila melanogaster. ETO, also called MTG8 (myeloid translocation gene on 8) has no overall homology to known proteins, but it contains two DNA-binding zinc finger motifs and several regions that are proline- and serine-rich. Both AML1 and ETO are thought to be transcription factors because the motifs they contain are found in other transcription factors. Both genes are transcribed from telomere to centromere, and cytogenetic analysis of variant translocations has shown that the critical junction always conserved is on the derivative 8 chromosome. The rearrangement between the two chromosomes results in a fusion gene that contains the 5' region of AML1 including that homologous to runt fused to almost all of ETO. The fusion transcript from the der(8) chromosome is consistently detected in patients with the t(8;21). The translocation can be detected at the molecular level with selected genomic DNA probes from chromosome 21 and from chromosome 8 near the breakpoint in 80-100% of the t(8;21) patients at diagnosis and in relapse, and with reverse transcriptase-polymerase chain reaction (RT-PCR) in all of the patients at diagnosis and in long-term remission. These results indicate that leukemic clones are still circulating in patients who have been in remission for as long as 8 years.
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PMID:The AML1 and ETO genes in acute myeloid leukemia with a t(8;21). 781 94

The PEBP2 alpha A and PEBP2 alpha B genes encode the DNA-binding subunit of a murine transcription factor, PEBP2, which is implicated as a T-cell-specific transcriptional regulator. These two related genes share the evolutionarily conserved region encoding the Runt domain. PEBP2 alpha B is the murine counterpart of human AML1, which is located at the breakpoints of the 8;21 and 3;21 chromosome translocations associated with acute myeloid leukemia. Northern (RNA) blots of various adult mouse tissues revealed that the levels of expression of both genes were most prominent in the thymus. Furthermore, transcripts of PEBP2 alpha A and mouse AML1/PEBP2 alpha B were detected in T lymphocytes in the thymuses from day 16 embryos and newborns, as well as 4-week-old adult mice, by in situ hybridization. The expression of the genes persisted in peripheral lymph nodes of adult mice. The transcripts were detected in all the CD4- CD8-, CD4+ CD8+, CD4+ CD8-, and CD4- CD8+ cell populations. The results indicated that both genes are expressed in T cells throughout their development, supporting the notion that PEBP2 is a T-cell-specific transcription factor. Transcripts of mouse AML1/PEBP2 alpha B were also detected in day 12 fetal hematopoietic liver and in the bone marrow cells of newborn mice. The implication of mouse AML1/PEBP2 alpha B expression in hematopoietic cells other than those of T-cell lineage is discussed in relation to myeloid leukemogenesis.
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PMID:Expression of the Runt domain-encoding PEBP2 alpha genes in T cells during thymic development. 786 57

Fluorescence in situ hybridization (FISH) and/or RNA-based polymerase chain reaction (RT-PCR) were used to analyze the breakpoints within the AML1 gene and the AML1 fusion transcripts in t(8;21) acute myeloid leukemia (AML). Twenty-two patients presented with the simple t(8;21)(q22;q22) and one with a complex variant t(8;2;16;21). In eight cases we used FISH with AML1 cosmid probes on metaphase chromosomes as well as RT-PCR to detect the junctions of MAL1/CDR (ETO,MTG8). Five cases were analyzed by FISH alone and ten cases by RT-PCR alone. By FISH we could identify three groups according to the distribution of the fluorescent signal. Signals were found in group 1 on chromosomes 21 and 21q+, in group 2 on chromosomes 21, 21q+ and 8q- and in group 3 on chromosomes 21 and 8q-. In all groups we could detect an identical AML1/CDR fusion transcript. This transcript showed splicing of AML1 exon 5 onto CDR. Thus regardless of the heterogeneity suggested by FISH, all the breakpoints in the AML1 gene were clustered in the same intro between exons 5 and 6. Our results bring to over one hundred the number of t(8;21) cases in which an identical translocation could be detected at molecular level by RT-PCR. The high sensitivity of the technique makes it suitable for the diagnosis of this translocation in different stages of the disease. The impact of the molecular detection of t(8;21) cells in clinical remission as far as the treatment and the management of the disease are concerned deserves further discussion.
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PMID:Identical fusion transcript associated with different breakpoints in the AML1 gene in simple and variant t(8;21) acute myeloid leukemia. 786 65

In the translocation (8;21)(q22;q22) associated with acute myelogenous leukemia (AML), part of the long arm of chromosome 8 is reciprocally translocated onto chromosome 21. At the molecular level the translocation results in the fusion of the 5' region of the AML1 gene on chromosome 21 and almost the entire CDR gene (also ETO or MTG8) on chromosome 8. The translocation can be demonstrated by techniques such as Southern blot analysis of DNA and reverse transcription-polymerase chain reaction (RT-PCR) analysis of mRNA. Neither of these methods demonstrates the translocation in individual cells. To detect the translocation at the single cell level, we used two probes, a cosmid clone containing the first five exons of AML1 and a P1 clone containing the entire CDR gene. Hybridization of the two probes to the distal and proximal side of the translocation breakpoint on chromosome 8 was expected to highlight the 8q-derivative in an interphase cell. To demonstrate the ability to identify the translocation in interphase cells using two-color FISH, these two probes were hybridized simultaneously to the Kasumi-1 cell line containing the 8;21 translocation and to t(8;21)-positive leukemic cells from a patient. Each probe was detected with a different color so that their relationship in the sample could be determined within the same interphase cell. Simultaneous hybridization of the CDR and AML1 probes to interphase cells resulted in one red and one green hybridization signal randomly located in the cell, from the hybridization to the normal chromosomes (8, 21), and one red-green pair of signals from the close hybridization of the two probes to the fusion gene on the derivative 8q-chromosome, indicating the translocation. This technique may be a useful complement for the analysis of the t(8;21), since critical information can be obtained from samples not suited for RT-PCR and conventional cytogenetic techniques. In addition, it may be useful for the assessment of minimal residual disease where RT-PCR is of limited value.
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PMID:Interphase cytogenetics of the t(8;21)(q22;q22) associated with acute myelogenous leukemia by two-color fluorescence in situ hybridization. 788 21

The AML-1/CBF beta transcription factor complex is targeted by both the t(8;21) and the inv(16) chromosomal alterations, which are frequently observed in acute myelogenous leukemia. AML-1 is a site-specific DNA-binding protein that recognizes the enhancer core motif TGTGGT. The t(8;21) translocation fuses the first 177 amino acids of AML-1 to MTG8 (also known as ETO), generating a chimeric protein that retains the DNA-binding domain of AML-1. Analysis of endogenous AML-1 DNA-binding complexes suggested the presence of at least two AML-1 isoforms. Accordingly, we screened a human B-cell cDNA library and isolated a larger, potentially alternatively spliced, form of AML1, termed AML1B. AML-1B is a protein of 53 kDa that binds to a consensus AML-1-binding site and complexes with CBF beta. Subcellular fractionation experiments demonstrated that both AML-1 and AML-1/ETO are efficiently extracted from the nucleus under ionic conditions but that AML-1B is localized to a salt-resistant nuclear compartment. Analysis of the transcriptional activities of AML-1, AML-1B, and AML-1/ETO demonstrated that only AML-1B activates transcription from the T-cell receptor beta enhancer. Mixing experiments indicated that AML-1/ETO can efficiently block AML-1B-dependent transcriptional activation, suggesting that the t(8;21) translocation creates a dominant interfering protein.
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PMID:The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation. 789 92

The WT1 gene encoding a zinc finger polypeptide is a tumor suppressor gene that plays a key role in the carcinogenesis of Wilms' tumor. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to examine relative levels of WT1 gene expression (defined in K562 cells as 1.00) in 45 patients with acute myelogenous leukemia (AML), 22 with acute lymphocytic leukemia (ALL), 6 with acute mixed lineage leukemia (AMLL), 23 with chronic myelogenous leukemia (CML), and 24 with non-Hodgkin's lymphoma. Significant levels of WT1 gene were expressed in all leukemia patients and for CML the levels increased as the clinical phase progressed. In striking contrast with acute leukemia, the levels of WT1 gene expression for NHL were significantly lower or even undetectable. Clear correlation was observed between the relative levels of WT1 gene expression (< 0.6 v > or = 0.6) and the prognosis for acute leukemia (AML, ALL, and AMLL). Patients with less than 0.6 levels had significantly higher rates of complete remission (CR), disease-free survival, and overall survival than those with > or = 0.6 levels, whereas CR could not be induced in any of the 7 patients with acute leukemia having greater than 1.0 levels of WT1 gene expression. The quantitation of the WT1 gene expression made it possible to detect minimal residual disease (MRD) in acute leukemia regardless of the presence or absence of tumor-specific DNA markers. Continuous monitoring of the WT1 mRNA was performed for 9 patients with acute leukemia. In 4 patients, MRD was detected 2 to 8 months before clinical relapse became apparent. In 2 other patients, the WT1 mRNA gradually increased after discontinuation of chemotherapy. No MRD was detected in the remaining 3 patients with AML who received intensive induction and consolidation therapy. Simultaneous monitoring of MRD by RT-PCR using primers for specific DNA markers in 3 patients (2 AML-M3 with PML/RAR alpha, and 1 AML-M2 with AML1/ETO) among these 9 patients detected MRD comparable with that obtained from quantitation of WT1 gene expression. In a patient with acute promyelocytic leukemia, the limits of leukemic cell detection by RT-PCR using either WT1 or promyelocytic leukemia/retinoic acid receptor-alpha gene primers were 10(-3) to 10(-4) and 10(-4) for bone marrow, and 10(-5) and 10(-4) for peripheral blood, respectively. Therefore, we conclude that WT1 is a new prognostic factor and a new marker for the detection of MRD in acute leukemia.
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PMID:WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. 794 79

The translocation from chromosome 8 to chromosome 21, t(8;21), associated with acute myeloid leukemia results in production of an AML1/MTG8(ETO) fusion transcript. The product of the AML1 gene contains an evolutionarily conserved 128-amino acid region referred to as the "Runt domain," which is necessary for binding to DNA at the PEBP2 site. A fragment of the AML1 protein containing mainly the Runt domain and the antisense oligonucleotide complementary to the fusion transcript strongly inhibited the growth and induced differentiation of cell lines derived from acute myeloid leukemia containing t(8;21). These results indicate that the transcriptional regulation through the PEBP2 site is critically important for growth and differentiation of t(8;21) leukemic cells and that the product of the chimeric gene is responsible for the maintenance of the leukemic phenotype.
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PMID:Growth inhibition and induction of differentiation of t(8;21) acute myeloid leukemia cells by the DNA-binding domain of PEBP2 and the AML1/MTG8(ETO)-specific antisense oligonucleotide. 797 30


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