Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ewing tumours (ET), including Ewing's sarcoma and peripheral primitive neuroectodermal tumour, are well characterised at the molecular level by a unique chromosomal rearrangement which fuses the EWS gene to one of two closely related ETS proto-oncogenes, FLI-1 or ERG. Expression of the resulting chimaeric transcripts can be readily detected by reversed transcriptase polymerase chain reaction (RT-PCR). This approach led to the identification of a number of different exon combinations at the junction site of coding sequences. The physiological consequences of the observed variability in the hinge region of EWS chimaeric proteins are not known. We have analysed tumour-derived material from 30 ET patients with well-documented clinical course (18 with localised and 12 with metastatic disease at diagnosis) for the presence of EWS/FLI-1 or EWS/ERG RNA. Karyotypes were obtained in 21 out of 27 cases and analysed by routine cytogenetics. A chromosome 22 rearrangement was demonstrated in 18 cases (67%). In contrast, RT-PCR revealed the presence of chimaeric transcripts in 28 tumours (93%), with fusions of EWS exon 7 to FLI-1 exons 6 (19/28), 5 (4/28) and 7 (1/28). In addition, EWS/FLI-1 exon combinations 10/5 and 9/4 were observed in one case each. In the last tumour, the presence of at least four additional splicing variants corresponding to fusion of EWS exon 7 to FLI-1 exons 4, 6, 8 and 9 was demonstrated. Two tumours expressed EWS/ERG fusion transcripts involving EWS exon 7 and ERG exon 6. In this study, EWS/FLI-1 exon combinations 7/6 (type I) predominated over 7/5 (type II) in localised ET (14 versus 1) and were more abundant in tumours affecting the long bones (9 versus 0), whereas in central axis tumours and metastatic disease there was only little difference in the frequency of the two types. So far, no correlations between different chimaeric EWS transcripts and any other clinical parameters have been identified.
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PMID:Variability of EWS chimaeric transcripts in Ewing tumours: a comparison of clinical and molecular data. 752 4

The EWS gene is fused in Ewing sarcoma-like tumors by a chromosomal translocation to one of the four ETS-family genes: FLI1, ERG, ETV1, and E1AF. The orientation of EWS and FLI1 on chromosomes 22 and 11, respectively, is 5' centromeric and 3' telomeric, whereas that of ERG on chromosome 21 is the reverse. Although 10% of Ewing-family tumors express the EWS-ERG fusion transcript, there have been no reports on tumors with t(21;22)(q22;q12) identified by banding cytogenetics. We found the karyotype 50, XY, +8, +8, +12, +mar in all metaphase cells from a tumor. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis performed on the tumor and direct sequencing of the products identified the EWS-ERG fusion transcript. Subsequent two-color fluorescence in situ hybridization (FISH) analysis with EWS and ERG clones showed the fused signals on the der(21) chromosome, but no ERG signals on the chromosome 22 homologs. Thus, our RT-PCR and FISH analyses indicated that the chromosome 22 fragment containing the 5' portion of EWS had been inverted and inserted into chromosome 21 and had fused to the 3' portion of ERG. This subtle chromosome aberration could not be identified by routine cytogenetics. A chromosomal inversion/insertion has also been described in acute leukemia with the MLL-AF10 fusion gene, and this may be a common pathway for producing fusion of reverse-oriented genes in leukemias and solid tumors.
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PMID:EWS-ERG fusion transcript produced by chromosomal insertion in a Ewing sarcoma. 907 76

In more than 95% of patients, the Ewing family of tumors (ET) has chimeric transcripts caused by fusion of the EWS gene to either FLI1 or ERG. The presence of specific EWS-FLI1 or EWS-ERG transcripts in peripheral blood (PB) samples of patients being treated for ET was prospectively evaluated, and these data were correlated to their clinical status. The authors studied 113 PB samples from 28 patients with ET. Treatment included chemotherapy, radiotherapy, and surgical excision of tumor after induction therapy. PB samples were taken prospectively at least 2 weeks after resection of tumor. Nested reverse-transcriptase polymerase chain reaction (RT-PCR) followed by Southern blot was performed in all samples. Resected tumors were reviewed for the degree of response to chemotherapy and volume. Seventy-seven PB samples from 28 patients had EWS-FLI1/ERG transcripts. In 11 patients, PB samples became negative with treatment, and, in 5 of them, the samples remained negative throughout the study. Samples taken during progression were always positive and, in 4 patients, became positive before progression was clinically evident. All patients with transcripts other than EWS-FLI1 type 1 (n = 3) died from tumor progression. This is a sensitive assay to monitor circulating tumor cells in Ewing tumors. The preliminary data suggest that progression is preceded by positive samples and may be related to specific transcript types.
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PMID:Ewing family tumors: potential prognostic value of reverse-transcriptase polymerase chain reaction detection of minimal residual disease in peripheral blood samples. 983 70

During embryogenesis cells make appropriately timed developmental decisions. Both 'hourglass-like' and 'clock-like' mechanisms have been demonstrated to act as timers in early development. The cell cycle rhythm, using feedback circuits to drive cells unidirectionally through checkpoints, is an example of a clock-like timer, but how it operates to time developmental events is unclear. In other cell types, cyclic oscillations in K+ channel activity, which parallel cell cycle and circadian rhythms, may be part of the timing mechanism. Changes in K+ oscillations accompany key developmental transitions and oncogenic transformation. Channel blockade interferes pharmacologically with cell cycle initiation or progression, whereas channel over-expression can be oncogenic. K+ channel activity also exists in early mouse oocytes through to at least the blastocyst stage, and it oscillates in phase with the developmental cell cycles, being high in M/G1 and low in S/G2. It resembles physiologically the activity of the K+ channels of the eag- or erg-like families. Reverse transcriptase-polymerase chain reaction of mouse oocytes has revealed the presence of transcripts encoding both EAG- and ERG-like proteins throughout preimplantation development. Channel activity continues to oscillate with a cell cycle periodicity in embryos from which the nucleus has been removed, or after inhibition by puromycin of the cyclin B-cyclin-dependent kinase 1 driven component of the chromosomal cycle. Channel oscillatory activity thus appears to be able to function autonomously of the chromosomal cycle and may represent a distinct oscillatory timing activity with possible developmental significance.
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PMID:tiK+ toK+: an embryonic clock? 1154 67

This study reports a 1-year-old boy with precursor B cell acute lymphoblastic leukemia (ALL) carrying t(16;21)(p11;q22). Reverse transcriptase-polymerase chain reaction (RT-PCR) and direct sequence analysis showed TLS/FUS-ERG chimeric mRNA with a novel junctional pattern of exon 7 of TLS/FUS and exon 6 of ERG. He did not respond to ALL-oriented therapy. Complete remission (CR) was achieved by chemotherapy oriented for acute myeloid leukemia. Allogenic bone marrow transplantation was done and he has been in CR for 24 months. TLS/FUS-ERG chimeric mRNA was not detected after CR. This is the first report of an ALL patient with a TLS/FUS-ERG fusion transcript.
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PMID:TLS/FUS-ERG fusion gene in acute lymphoblastic leukemia with t(16;21)(p11;q22) and monitoring of minimal residual disease. 1626 89

We report on a case of pediatric acute myelocytic leukemia showing 47,XX,+10,t(16;21)(p11;q22) that resulted in an unusual TLS/FUS-ERG chimeric transcript. The leukemic cells showed erythrophagocytosis, positive reactions for myeloperoxidase and Sudan black B stains, and negative reactions for periodic acid-Schiff and alpha-naphtyl butyrate esterase stains as well as expression of myeloid antigens. We also confirmed a very rare type of TLS/FUS-ERG chimeric transcript by fusion of the 5' part of the TLS/FUS gene in chromosome 16p11 and the 3' part of the ERG gene in chromosome 21q22 using reverse-transcriptase polymerase chain reaction and direct sequencing. After achieving a complete remission with two cycles of induction chemotherapy, the patient received an umbilical cord blood transplantation.
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PMID:Unusual type of TLS/FUS-ERG chimeric transcript in a pediatric acute myelocytic leukemia with 47,XX,+10,t(16;21)(p11;q22). 1673 20

The recent identification of fusion genes involving ETS family members in human prostate adenocarcinoma has confirmed the hypothesis that recurrent specific aberrations such as fusion genes may be as frequent in epithelial tumors as they are in leukemias and sarcomas. However, reciprocal translocations with fusion genes are often not detectable in carcinomas by conventional karyotyping because of additional complex chromosomal abnormalities. We retrospectively analyzed a large series of formalin-fixed, paraffin-embedded samples including 55 prostate carcinomas and 11 benign prostate tumors. We identified the fusion gene TMPRSS2-ERG by reverse-transcriptase polymerase chain reaction (RT-PCR) in 40/55 carcinomas (72%). Our study demonstrates that the detection of ETS fusion gene by RT-PCR is feasible on formalin-fixed and paraffin-embedded samples. No significant association between the presence of the fusion gene and any clinical feature, such as preoperative serum prostate-specific antigen (PSA) level (PSA>20 or PSA< or =20), pTNM stage including capsule invasion, seminal vesicle invasion, and lymph nodes metastases, or recurrence was observed in our series.
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PMID:Detection of the TMPRSS2-ETS fusion gene in prostate carcinomas: retrospective analysis of 55 formalin-fixed and paraffin-embedded samples with clinical data. 1847 93

PURPOSE To determine the prognostic importance of the meningioma 1 (MN1) gene expression levels in the context of other predictive molecular markers, and to derive MN1 associated gene- and microRNA-expression profiles in cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS MN1 expression was measured in 119 untreated primary CN-AML adults younger than 60 years by real-time reverse-transcriptase polymerase chain reaction. Patients were also tested for FLT3, NPM1, CEBPA, and WT1 mutations, MLL partial tandem duplications, and BAALC and ERG expression. Gene- and microRNA-expression profiles were attained by performing genome-wide microarray assays. Patients were intensively treated on two first-line Cancer and Leukemia Group B clinical trials. Results Higher MN1 expression associated with NPM1 wild-type (P < .001), increased BAALC expression (P = .004), and less extramedullary involvement (P = .01). In multivariable analyses, higher MN1 expression associated with a lower complete remission rate (P = .005) after adjustment for WBC; shorter disease-free survival (P = .01) after adjustment for WT1 mutations, FLT3 internal tandem duplications (FLT3-ITD), and high ERG expression; and shorter survival (P = .04) after adjustment for WT1 and NPM1 mutations, FLT3-ITD, and WBC. Gene- and microRNA-expression profiles suggested that high MN1 expressers share features with high BAALC expressers and patients with wild-type NPM1. Higher MN1 expression also appears to be associated with genes and microRNAs that are active in aberrant macrophage/monocytoid function and differentiation. CONCLUSION MN1 expression independently predicts outcome in CN-AML patients. The MN1 gene- and microRNA-expression signatures suggest biologic features that could be exploited as therapeutic targets.
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PMID:Prognostic importance of MN1 transcript levels, and biologic insights from MN1-associated gene and microRNA expression signatures in cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. 1945 32

We report two childhood cases of acute leukemia with t(16;21)(p11.2;q22) and FUS-ERG rearrangements. Patient 1 (14 years old) was initially diagnosed with acute myeloid leukemia. Chromosome study showed a t(16;21)(p11.2;q22) clone in more than one third of the cells analyzed, and further investigation with reverse-transcriptase polymerase chain reaction, cloning, and sequencing confirmed FUS-ERG rearrangement (type B). Patient 2 (8 months old) was diagnosed with acute lymphoblastic leukemia (ALL) on the basis of bone marrow morphology and immunophenotyping. Chromosome study revealed a 45,XY,-16,der(21)t(16;21)(p11.2;q22) in 50% of the cells analyzed. Further studies for the detection of a FUS-ERG chimeric transcript were conducted, and an unusual type of FUS-ERG rearrangement was discovered, which has been reported in only three patients including a 1-year-old infant with ALL. Although more clinical studies are necessary, we believe that a possible association between ALL and a specific type of FUS-ERG fusion transcript might be considered, especially in childhood cases with t(16;21).
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PMID:Two childhood cases of acute leukemia with t(16;21)(p11.2;q22): second case report of infantile acute lymphoblastic leukemia with unusual type of FUS-ERG chimeric transcript. 2062 Jun 4

The Ewing sarcoma (ES) family of tumors is characterized by nonrandom chromosomal translocations involving the EWSR1 gene on chromosome 22 with one of the members of the ETS family of transcription factors. The majority of ES tumors are characterized by a balanced translocation t(11;22)(q24;q12), which results in the fusion of the 5' portion of EWSR1 gene with the 3'end of the FLI1 gene. Fusions with ERG, another member of the ETS family, occur in less than 10% of ES tumors, and can arise through complex chromosomal rearrangements. Here, we report a case of a 5-year-old female with an ES tumor in the thoracic region. G-banding and spectral karyotyping analysis demonstrated 46,XX,t(1;21;7)(q25;q22.3;q22). Metaphase fluorescence in situ hybridization (FISH) using the EWSR1 break-apart probe demonstrated a normal signal on both apparently normal chromosomes 22, and an additional EWSR1-5' signal on the derivative chromosome 21. Reverse-transcriptase polymerase chain reaction analysis of RNA isolated from the tumor demonstrated a EWSR1-ERG fusion transcript, fusing exon 7 of EWSR1 and exon 11 of ERG. These results are consistent with an additional copy of the 5' portion of EWSR1, which inverted and then inserted on chromosome 21 and fused to the 3' end of ERG. To our knowledge, this is the first report of a EWSR1-ERG fusion in an ES tumor with an apparently duplicated 5' portion of EWSR1, and with a complex translocation involving chromosomes 1, 7, and 21. This case adds to the spectrum of genetic rearrangements identified in ES tumors.
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PMID:Complex rearrangement of chromosomes 1, 7, 21, 22 in Ewing sarcoma. 2063 68


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