Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

We report the case of a patient in whom the diagnosis of Ewing sarcoma arising from a soft tissue was made after successful treatment of diffuse large B-cell lymphoma. A 65-year-old woman presented with a rapidly growing mass in her left scapular region 8 years after successful chemotherapy with the cyclophosphamide, hydroxydaunomycin hydrochloride, vincristine, prednisolone regimen for diffuse large B-cell lymphoma. Computed tomographic examination and magnetic resonance imaging of the thorax revealed an intramuscular tumour measuring 40 mm in size in the left scapular region. Histopathological examination of an open biopsy specimen revealed a small round cell tumour that showed positive staining for CD99. Fluorescence in situ hybridization showed a split signal by a break-apart probe for the EWS gene in chromosome 22q12. Reverse transcriptase-polymerase chain reaction confirmed the expression of EWS-FLI1 fusion transcripts. Based on these findings, the patient was diagnosed as having secondary Ewing sarcoma. Despite adjuvant chemotherapy, however, she died of pulmonary metastases 2 years after the diagnosis of Ewing sarcoma. Therapy-related haematological malignancies with balanced translocations have been reported previously. A mechanism similar to that underlying the development of secondary malignancy might explain the occurrence of this solid cancer.
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PMID:Ewing sarcoma arising after treatment of diffuse large B-cell lymphoma. 2347 35

Alternative splicing plays a key role in the DNA damage response and in cancer. Ewing Sarcomas (ES) are aggressive tumors caused by different chromosomal translocations that yield in-frame fusion proteins driving transformation. RNA profiling reveals genes differentially regulated by UV light irradiation in two ES cell lines exhibiting different sensitivity to genotoxic stress. In particular, irradiation induces a new isoform of the RNA helicase DHX9 in the more sensitive SK-N-MC cells, which is targeted to nonsense-mediated decay (NMD), causing its downregulation. DHX9 protein forms a complex with RNA polymerase II (RNAPII) and EWS-FLI1 to enhance transcription. Silencing of DHX9 in ES cells sensitizes them to UV treatment and impairs recruitment of EWS-FLI1 to target genes, whereas DHX9 overexpression protects ES cells from genotoxic stress. Mechanistically, we found that UV light irradiation leads to enhanced phosphorylation and decreased processivity of RNAPII in SK-N-MC cells, which in turn causes inclusion of DHX9 exon 6A. A similar effect on DHX9 splicing was also elicited by treatment with the chemotherapeutic drug etoposide, indicating a more general mechanism of regulation in response to DNA damage. Our data identify a new NMD-linked splicing event in DHX9 with impact on EWS-FLI1 oncogenic activity and ES cell viability.
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PMID:Genotoxic stress inhibits Ewing sarcoma cell growth by modulating alternative pre-mRNA processing of the RNA helicase DHX9. 2645 Sep

A 20-year-old man developed a soft tissue mass in his right upper arm and, 3 months later, was referred to our hospital. The tumor cells showed brisk mitotic activity and a large amount of cytoplasmic glycogen was demonstrated with periodic acid Schiff stain. A diagnosis of atypical Ewing sarcoma was made. Chemotherapy according to the VACA protocol, comprising vincristine, actinomycin D, cyclophosphamide and doxorubicin was started. The chemotherapy was effective and a limb salvage procedure was performed by implantation of an autoclaved bone after wide tumor excision. During the postoperative chemotherapy, a local recurrence and multiple metastases developed, and the patient died due to disease progression. Fourteen years later, this tumor sample, preserved in a deep-freeze, was analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR) to detect the fusion gene. This tumor had an EWS exon 7 to FLI1 exon 6 fusion transcript. Moreover, metaphase and microarray comparative genomic hybridization (CGH) was done to detect chromosomal instabilities. Many gains and losses were noted on metaphase CGH, and MYCL amplification was identified on microarray CGH.
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PMID:Amplification of MYCL in Atypical Ewing Tumor. Analysis of Metaphase and Microarray Comparative Genomic Hybridization. 3139 6

There is a need to develop novel approaches to improve the balance between efficacy and toxicity for transcription factor-targeted therapies. In this study, we exploit context-dependent differences in RNA polymerase II processivity as an approach to improve the activity and limit the toxicity of the EWS-FLI1-targeted small molecule, mithramycin, for Ewing sarcoma. The clinical activity of mithramycin for Ewing sarcoma is limited by off-target liver toxicity that restricts the serum concentration to levels insufficient to inhibit EWS-FLI1. In this study, we perform an siRNA screen of the druggable genome followed by a matrix drug screen to identify mithramycin potentiators and a synergistic "class" effect with cyclin-dependent kinase 9 (CDK9) inhibitors. These CDK9 inhibitors enhanced the mithramycin-mediated suppression of the EWS-FLI1 transcriptional program leading to a shift in the IC50 and striking regressions of Ewing sarcoma xenografts. To determine whether these compounds may also be liver protective, we performed a qPCR screen of all known liver toxicity genes in HepG2 cells to identify mithramycin-driven transcriptional changes that contribute to the liver toxicity. Mithramycin induces expression of the BTG2 gene in HepG2 but not Ewing sarcoma cells, which leads to a liver-specific accumulation of reactive oxygen species (ROS). siRNA silencing of BTG2 rescues the induction of ROS and the cytotoxicity of mithramycin in these cells. Furthermore, CDK9 inhibition blocked the induction of BTG2 to limit cytotoxicity in HepG2, but not Ewing sarcoma cells. These studies provide the basis for a synergistic and less toxic EWS-FLI1-targeted combination therapy for Ewing sarcoma.
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PMID:CDK9 Blockade Exploits Context-dependent Transcriptional Changes to Improve Activity and Limit Toxicity of Mithramycin for Ewing Sarcoma. 3212 64


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