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 t(8;21) reciprocal chromosomal translocation is frequently associated with M2b type of acute myeloid leukemia (AML). Recently, two genes, MTG8 on chromosome 8 and AML1 on chromosome 21, were found. The t(8;21) translocation resulted in rearrangements of the two genes and formation of AML1/MTG8 fusion gene. To clarify the molecular characteristics of AML-M2b, we studied 41 patients with AML-M2b. By Southern blot and hybridization, the rearrangements of AML1 and MTG8 genes were detected in 24 of 30 and 22 of 28 patients, respectively. By means of reverse transcription and polymerase chain reaction (RT-PCR), the AML1/MTG8 chimeric transcript was found in all 37 patients. In 4 patients with AML-M2b of normal karyotype, AML1/MTG8 fusion mRNA and/or rearrangements of AML1 and MTG8 genes were detected. However, among 31 patients with other types of AML, these abnormalities were found in only one patient with AML-M6. These results suggest that rearrangements of AML1, MTG8 genes and/or AML1/MTG8 fusion gene could be regarded as gene marker of AML-M2b that can be applied in the diagnosis and monitoring of therapy and minimal residual disease.
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PMID:[Rearrangements and fusion gene of AML1 and MTG8 in acute myeloid leukemia M2b]. 755 57

The t(8;21) is a frequent chromosome abnormality in acute myeloid leukemia (AML), particularly associated with M2 of the French-American-British (FAB) classification, but also found in a few patients with myelodysplastic syndrome (MDS). The two genes involved in the t(8;21) have been recently isolated and the cDNA of the AML1/ETO fusion gene identified. We have investigated a series of AML and MDS patients by a reverse transcriptase-polymerase chain reaction (RT-PCR) and analyzed the clinical and laboratory features of leukemia with t(8;21). The t(8;21) was only found in a subset of M2, which had the clinical and hematological features distinct from those M2 without t(8;21). M2 with t(8;21) was associated with a significantly higher myeloid differentiation and with a good response to chemotherapy. Moreover, among the patients with refractory anemia with excess of blasts in transformation (RAEB-T) the t(8;21) was also significantly associated with a higher myeloid differentiation and a good response to chemotherapy. M2 patients with t(8;21) could be distinguished on a number of hematological parameters, eg white blood cell count and percentage of bone marrow myeloblasts and promyelocytes, from RAEB-T carrying the t(8;21). Based on these findings we suggest that leukemia patients carrying t(8;21) can be grouped into two types; overt acute myeloid leukemia (M2) and smoldering or slowly evolving myeloid leukemia.
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PMID:High degree of myeloid differentiation and granulocytosis is associated with t(8;21) smoldering leukemia. 763 Jan 88

The WT 1 gene has been isolated as a tumor suppressor gene of Wilms' tumor. Using reverse transcriptase-polymerase chain reaction (RT-PCR), relative levels of the WT 1 gene expression was examined in 87 patients with acute leukemia, 25 with chronic myelogenous leukemia (CML), and 24 with non-Hodgkin's lymphoma (NHL). Significant levels of the WT 1 gene were expressed in all leukemia patients, and for CML the levels increased as the clinical phase progressed. No point mutations were found in the WT 1 gene when samples from 15 acute leukemia patients were subjected to PCR single-strand conformation polymorphism analysis. In striking contrast to acute leukemia, the levels of WT1 gene expression for NHL were significantly low or even undetectable. The levels of WT 1 gene expression inversely correlated with the prognosis of acute leukemia. The quantification of the WT 1 gene expression made it possible to detect minimal residual disease (MRD) in acute leukemia regardless of the presence of absence of tumor-specific DNA markers. Simultaneous monitoring of MRD by RT-PCR using primers for specific DNA markers in four patients (two AML-M3 with PML/RAR-alpha, one AML-M2 with AML1/ETO, and one CML with bcr/abl) detected MRD comparable to that obtained from quantitation of WT 1 gene expression. In a patient with acute promyelocytic leukemia, the limits of leukemic cell detection by RT-PCR using either WT 1 or PML/RAR-alpha gene primers were 10(-3)-10(-4) and 10(-4) for bone marrow, and 10(-5) and 10(-4) for peripheral blood, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[WT 1 and leukemia]. 764 50

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

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

In the t(8;21) of acute myeloid leukemia (AML) M2, breakpoints are clustered on both chromosomes. The chromosome 21 breakpoint cluster region (bcr) falls within the runt locus, in the intron immediately downstream of the exons encoding an evolutionary conserved domain (the runt box). Transcripts in which the runt box is fused in frame to a novel sequence derived from chromosome 8 (MTG8) have been previously identified and have been assumed to constitute a critical leukemogenic event. Here we show physical linkage of the chromosome 8 bcr to the MTG8 locus. Unexpectedly, not only does the bcr map upstream of the most 5' MTG8 exon found in runt/MTG8 fusion transcripts, but it also maps upstream of a further 5' exon. In addition, we demonstrate the presence of alternative transcripts, originating from the der(8) chromosome, in which runt is out of frame with MTG8. Thus, runt truncation per se, rather than its fusion to MTG8, may be the crucial leukemogenic event.
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PMID:Alternative, out-of-frame runt/MTG8 transcripts are encoded by the derivative (8) chromosome in the t(8;21) of acute myeloid leukemia M2. 791 24

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


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