Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035412 (rhabdomyosarcoma)
 6,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36;q14) are characteristic of alveolar rhabdomyosarcoma, a pediatric soft tissue cancer related to the striated muscle lineage. These translocations rearrange PAX3 and PAX7, members of the paired box transcription factor family, and juxtapose these genes with FKHR, a member of the fork head transcription factor family. This juxtaposition generates PAX3-FKHR and PAX7-FKHR chimeric genes that are expressed as chimeric transcripts that encode chimeric proteins. The fusion proteins, which contain the PAX3/PAX7 DNA binding domain and the FKHR transcriptional activation domain, activate transcription from PAX-binding sites with higher potency than the corresponding wild-type PAX proteins. This increased function results from the insensitivity of the FKHR activation domain to inhibitory effects of N-terminal PAX3/PAX7 domains. In addition to altered function, the fusion products are expressed in ARMS tumors at higher levels than the corresponding wild-type PAX products due to two distinct mechanisms. The PAX7-FKHR fusion is overexpressed as a result of in vivo amplification while the PAX3-FKHR fusion is overexpressed due to a copy number-independent increase in transcriptional rate. Finally, though FKHR subcellular localization is regulated by an AKT-dependent pathway, the fusion proteins are resistant to these signals and show exclusively nuclear localization. Therefore, these translocations alter biological activity at the levels of protein function, gene expression, and subcellular localization with the cumulative outcome postulated to be aberrant regulation of PAX3/PAX7 target genes. This aberrant gene expression program is then hypothesized to contribute to tumorigenic behavior by impacting on the control of growth, apoptosis, differentiation and motility.
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PMID:Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma. 1160 23

In this investigation, we selected PAX3/FKHR and PAX7/FKHR fusion transcript-positive and -negative alveolar rhabdomyosarcomas (ARMSs) and embryonal rhabdomyosarcomas (ERMSs) with and without anaplastic features, to ascertain genomic imbalance differences and/or similarities within these histopathologic and genetic rhabdomyosarcoma (RMS) variants. Comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) studies were performed on 45 rhabdomyosarcoma specimens consisting of 23 ARMSs and 22 ERMSs (12 ERMS cases were included from an earlier study). The anaplastic variant of RMS has not previously been subjected to CGH analysis. Overall, the most prominent imbalances were gain of chromosomes or chromosomal regions 2/2q (40%), 7/7q (31%), 8/8p (53%), 11/11q (31%), 12q13-15 (49%), 13q14 (22%), and 20/20p (31%), and loss of 1p36 (27%), 3p14-21 (22%), 9q21-22 (33%), 10q22-qter (18%), 16q (27%), 17p (22%), and 22 (22%). These gains and losses were distributed equally between ARMS and ERMS histologic subtypes (excluding 7/7q and 11/11q gain that were observed chiefly in ERMS), demonstrating that these entities are similar with respect to recurrent genomic imbalances. Moreover, genomic imbalances were also evenly distributed among the ARMS fusion transcript subtypes, providing evidence for a genetic kinship despite the absence of a fusion transcript in some cases. Genomic amplification was detected in 26% and 23% of the ARMS and ERMS cases, respectively (with nearly all of the latter subset exhibiting anaplastic features). One amplicon, involving 15q25-26, corresponds to the locus of the insulin-like growth factor type I receptor (IGF1R) gene. Amplification of IGF1R was confirmed molecularly in the cases exhibiting a 15q25-26 amplicon. In summary, these results indicate that genomic gains and losses involve alike chromosomes with similar frequencies within the histopathologic and genetic subtypes of rhabdomyosarcoma, that genomic amplification is frequent not only in the alveolar histologic subtype of rhabdomyosarcoma but also in ERMS with anaplasia, and that amplification of IGF1R possibly plays a role in the development or progression of a subset of rhabdomyosarcomas.
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PMID:Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. 1180 89

Rhabdomyosarcoma (RMS) is a soft tissue tumor of childhood frequently diagnosed between the first and fifth year of life. Children with the Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth syndrome characterized by exomphalos, macroglossia, and macrosomia, have an increased risk of developing childhood tumors including Wilms tumor, hepatoblastoma, neuroblastoma, and RMS. Although an association between RMS and the BWS is well accepted, only four cases have been reported to date, and of these, three were reported as embryonal RMS. Based on these data, an association between BWS and embryonal RMS has been proposed. We report three additional cases of BWS with RMS and review the clinical data for each patient as well as the pathology of their tumors. All three cases of BWS had histology consistent with alveolar RMS and were diagnosed at 6 weeks and 5 and 13 years of age. In two of these BWS cases, constitutional defects of 11p15 imprinting were demonstrated. Furthermore, cytogenetic analysis of the tumors did not detect the t(2;13) or t(1;13) translocations that generate the PAX3- or PAX7-FKHR fusion proteins common to alveolar RMS. These observations suggest that the development of alveolar RMS tumors in BWS may occur without the chromosomal rearrangement producing the PAX-FKHR fusion protein. In summary, we present three new cases of RMS demonstrating a new association between BWS and an uncommon subtype of alveolar RMS. The absence of the translocations commonly associated with alveolar rhabdomyosarcoma suggests a common 11p15 pathway for alveolar RMS and BWS.
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PMID:Association of alveolar rhabdomyosarcoma with the Beckwith-Wiedemann syndrome. 1182 61

PAX3 is a transcription factor important for neural, muscle, and facial development in vertebrates. To identify genes regulated by PAX3, we used a cyclic amplification and selection of targets (CASTing) strategy to isolate cis-regulatory elements bound by PAX3. CASTing libraries were constructed with mouse DNA fragments bound by mouse PAX3, and human genomic DNA fragments bound by human PAX3 and the fusion protein PAX3-FKHR. Approximately 1000 clones were sequenced from each of these three libraries. Numerous putative targets of PAX3 and PAX3-FKHR were identified and six genes, Itm2A, Fath, FLT1, TGFA, BVES, and EN2, were examined closely. The genomic DNA fragments near these genes contain PAX3 binding sites and confer PAX3-dependent regulation. The expression levels of these genes correlate with the PAX3 expression levels in mouse embryos or with PAX3-FKHR expression levels in rhabdomyosarcoma cell lines, and indicate they may be part of the PAX3 regulatory circuitry during embryogenesis and tumor formation.
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PMID:Identification of target genes regulated by PAX3 and PAX3-FKHR in embryogenesis and alveolar rhabdomyosarcoma. 1186 57

Rhabdomyosarcoma (RMS) is a family of soft tissue tumors that are associated with the skeletal muscle lineage and generally occur in the pediatric population. Based on histopathologic features, two subtypes, embryonal (ERMS) and alveolar (ARMS), were identified and associated with distinct clinical characteristics and genetic alterations. ARMS is associated with 2;13 or 1;13 chromosomal translocations, which generate PAX3-FKHR and PAX7-FKHR fusion products, respectively. These translocations result in altered expression, function, and subcellular localization of the fusion products relative to the wild-type proteins, and ultimately contribute to oncogenic behavior by modifying growth, differentiation, and apoptosis pathways. In contrast to the specific translocations found in ARMS, most ERMS cases have allelic loss at chromosome 11p15.5. Chromosome fragment transfer studies demonstrated that this region represses tumor cell growth, suggesting the presence of tumor suppressor gene(s) in this region. In both ERMS and ARMS, there is evidence of collaborating alterations that affect common targets, such as the p53 and RB pathways. One mechanism for perturbing these pathways involves amplification of genes such as MDM2 and CDK4; these amplification events occur frequently in ARMS but only rarely in ERMS. Therefore, despite similarities in the downstream targets of these genetic alterations, the striking cytogenetic and molecular differences between ARMS and ERMS indicate distinct molecular etiologies in these two subtypes.
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PMID:Molecular pathogenesis of rhabdomyosarcoma. 1217 Jul 81

Previous studies of the PAX3-FKHR and PAX7-FKHR gene fusions in alveolar rhabdomyosarcoma (ARMS) indicated that the corresponding fusiontranscripts are not detectable in 20% of ARMS cases. To investigate the genetic features of this ARMS subset, we identified 23 ARMS cases in which PAX3-FKHR and PAX7-FKHR transcripts were not detected by a standard sensitivity reverse transcription-PCR (RT-PCR) assay. Subsequent analysis with a high sensitivity RT-PCR assay identified low-level expression of PAX3-FKHR or PAX7-FKHR in three cases. Analysis with a Southern blot assay for PAX3 and PAX7 rearrangements and a fluorescence in situ hybridization assay for FKHR rearrangements identified three cases with variant fusions in which PAX3 or PAX7 is postulated to be joined to novel genomic loci. In one such case, RT-PCR analysis of candidate partners identified a fusion of PAX3 to AFX, which is highly similar in structure and function to FKHR. Additional fluorescence in situ hybridization analysis identified two cases in which a PAX3-FKHR or PAX7-FKHR genomic fusion is present but is not associated with a fusion transcript detectable by RT-PCR. Finally, our analyses of the PAX3, PAX7, and FKHR loci did not identify rearrangements in >50% of cases, consistent with the possibility that there is a true fusion-negative subset. In summary, our analysis of ARMS cases without characteristic PAX3-FKHR or PAX7-FKHR transcripts identified several genetically distinct subsets including low expression or atypical presentation of standard fusions, variant fusions with other genes, and possibly true fusion-negative cases.
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PMID:Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. 1218 29

Rhabdomyosarcomas (RMSs) are classified into embryonal (ERMS), alveolar (ARMS), and pleomorphic (PRMS) subtypes. ERMS, including botryoid variants, typically occurs in young children, ARMS typically occurs in older children and young adults, and PRMS occurs in older adults. Although ARMSs show thin fibrous bands separating nests of cells, abundant extracellular matrix production is rare in RMS. In the course of reviewing hyalinizing sarcomas we discovered a distinctive RMS in adults that closely mimicked osteosarcoma or chondrosarcoma because of the extensive matrix production. Four RMSs with hyalinized matrix were retrieved from our files. These cases were evaluated with respect to patient age and sex, tumor site and size, growth pattern, nuclear grade, cellularity, mitotic figures/20 high power fields, vascular invasion, necrosis, the presence of rhabdomyoblasts, multinucleated cells, and alveolar growth pattern. Immunohistochemistry for desmin, myogenin, MyoD1, actin, cytokeratin, S-100 protein, collagen II, and CD99 was performed. Reverse transcriptase polymerase chain reaction for the ARMS-associated PAX3/FKHR and PAX7/PKHF was also performed on three cases. The cases involved the forearm, hand, orbit, and nasopharynx of a 40-year-old woman, a 50-year-old man, an 18-year-old man, and a 21-year-old man, respectively. The tumors ranged from 3.7 to 8 cm and consisted of lobules and infiltrating cords of small round malignant cells embedded in a densely hyalinized matrix having both a chondroid and osteoid-like appearance. No definite lacunae or matrix calcification was present. An alveolar pattern was only present focally, and tumor giant cells were not present. One case had a single focus of rhabdomyoblastic differentiation with strap cells. Mitotic activity was >20 mitotic figures/20 high power fields in three of four cases. Immunohistochemically, one case strongly expressed desmin, whereas three cases expressed it focally, with a dot-like pattern. Myogenin was only focally positive, but MyoD1 was present in nearly every cell of each case. Two cases expressed actin and one expressed CD99. No case expressed cytokeratin, S-100 protein, or collagen II. Only one case contained adequate RNA for reverse transcriptase polymerase chain reaction, and this case was negative for the ARMS-associated gene fusions. Follow-up showed one patient to be dead of metastatic disease at 60 months despite intensive therapy, another patient to be disease free at 26 months, and the third patient to be disease free at 5 months. The fourth case is recent. These cases are a distinctive-appearing rhabdomyosarcoma easily mistaken for variants of chondrosarcoma, osteosarcoma, or even sclerosing epithelioid fibrosarcoma because of their hyalinizing appearance compounded by their typically focal and dot-like desmin expression. These four cases are essentially identical to the three unusual RMSs recently reported by Mentzel and Katenkamp as "sclerosing, pseudovascular rhabdomyosarcoma in adults." Although the focal alveolar architecture and the primitive cytologic appearance of these hyalinizing RMS suggest a relationship with ARMS, the presence of abundant strap cells in one case, the predominant expression of MyoD1 rather than myogenin, and the absence of ARMS-associated fusions genes point more strongly toward a variant of ERMS. However, the late adult age in two cases is unusual for both EMRS and ARMS, suggesting that sclerosing RMS may prove to be a distinct subtype of RMS. Study of additional cases will be necessary to more fully elucidate its place among RMS and its prognostic significance.
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PMID:Sclerosing rhabdomyosarcoma in adults: report of four cases of a hyalinizing, matrix-rich variant of rhabdomyosarcoma that may be confused with osteosarcoma, chondrosarcoma, or angiosarcoma. 1221 74

We hypothesized that the CXC chemokine receptor-4 (CXCR4)-stromal-derived factor-1 (SDF-1) axis may be involved in metastasis of CXCR4(+) tumor cells into the bone marrow and lymph nodes, which secrete the alpha-chemokine SDF-1. To explore this hypothesis, we phenotyped by fluorescence-activated cell sorter analysis various human tumor cell lines for expression of CXCR4 and found that it was highly expressed on several rhabdomyosarcoma (RMS) cell lines. We also observed that cell lines derived from alveolar RMS, which is characterized by recurrent PAX3- and PAX7-FKHR gene fusions and is associated with a poor prognosis, expressed higher levels of CXCR4 than lines derived from embryonal RMS. Furthermore, transfer of a PAX3-FKHR gene into embryonal RMS cell activates CXCR4 expression. Because alveolar RMS frequently metastasizes to the bone marrow and lymph nodes, it seems that the CXCR4-SDF-1 axis could play an important role in this process. These findings prompted us to determine whether SDF-1 regulates the metastatic behavior of RMS cells. Accordingly, we found that, although SDF-1 did not affect proliferation or survival of these cell lines, it induced in several of them (1) phosphorylation of mitogen-activated protein kinase p42/44; (2) locomotion; (3) directional chemotaxis across membranes covered by laminin, fibronectin, or Matrigel; (4) adhesion to laminin, fibronectin, and endothelial cells; and (5) increased MMP-2 and diminished tissue inhibitors of metalloproteinases secretion. The small-molecule CXCR4-specific inhibitor, T140, effectively blocked the in vitro responses of RMS cells to SDF-1. On the basis of these observations we suggest that the CXCR4-SDF-1 axis may play an important role in tumor spread and metastasis of RMS cells to bone marrow and that molecular strategies aimed at inhibiting this axis could thus prove to be useful therapeutic measures.
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PMID:CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. 1223 74

PAX3-FKHR is an oncogenic form of the developmental regulator Pax3 transcription factor. PAX3-FKHR results from a t(2,13) chromosomal translocation, a unique genetic marker of alveolar rhabdomyosarcoma. In this study, we showed that ectopic expression of PAX3-FKHR, but not Pax3, in fibroblasts altered cell cycle control and accelerated G(0)/G(1) to S cell cycle transition. PAX3-FKHR-expressing cells had reduced expression of p27(Kip1) protein, a key cell cycle regulator. The reduction in p27(Kip1) levels by PAX3-FKHR resulted from destabilization of p27(Kip1) as shown by cycloheximide treatment and in vivo pulse-chase labeling experiments. The reduced p27(Kip1) protein level in PAX3-FKHR-expressing cells was restored to the level of control cells by treatment with chemical inhibitors that specifically blocked 26 S proteasome activity. Along with the reduction in p27(Kip1) protein, PAX3-FKHR-expressing cells exhibited elevated expression of F-box Skp2 protein, a substrate-specific component of SCF (Skp1-Cullin-F box protein) ligase involved in the cell cycle-dependent control of p27(Kip1) ubiquitination and 26 S proteasome dependent degradation. Finally, we showed that ectopic expression of p27(Kip1) in PAX3-FKHR-expressing cells significantly reduced the proliferation and colony-forming potential of these cells, implicating that down-regulation of p27(Kip1) protein played an active role in the PAX3-FKHR-directed cell transformation.
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PMID:PAX3-FKHR transformation increases 26 S proteasome-dependent degradation of p27Kip1, a potential role for elevated Skp2 expression. 1240 4

Increased levels of glucose uptake and increased expression of the glucose transporter (GLUT) genes are characteristic features of tumors. In the muscle-derived tumor alveolar rhabdomyosarcoma (ARMS), a chromosomal translocation t(2:13) generates the PAX3/forkhead homolog in rhabdomyosarcoma (FKHR) oncoprotein. In muscle tissues, glucose transport is primarily mediated by GLUT4. However, the mechanisms that regulate GLUT4 gene expression in tumor tissues are largely unknown. Therefore, we evaluated the role of PAX3/FKHR in the regulation of GLUT4 gene expression in muscle tumorigenesis. GLUT4 mRNA and protein were detected in ARMS-derived human biopsies and in ARMS-derived RH30 myoblasts, which both express the PAX3/FKHR chimeric protein, but not in either C2C12 or embryonal rhabdomyosarcoma-derived myoblasts. GLUT4 was functionally active in RH30 cells, because insulin induced a 1.4-fold stimulation of basal 2-deoxyglucose uptake rates. Coexpression of PAX3/FKHR increased basal transcriptional activity from a GLUT4 promoter reporter (GLUT4-P) in C2C12, SaOS-2, and Chinese hamster ovary-K1 cells in a dose-dependent and tissue-specific manner. PAX3/FKHR mutants with deletions in either the homeodomain (DeltaHD) or the FKHR-derived activation domain (DeltaFKHR), or in which the PAX3-derived paired domain (PD) was point-mutated (PD-R56L), were unable to activate GLUT4-P. Progressive 5'-deletion analysis of GLUT4-P further identified a specific region of the promoter, -66/+163 bp, which retained about 65% of the full transactivation effect. EMSA studies established that the PAX3/FKHR protein directly and specifically binds to this region and to a shorter fragment, -4/+36 bp, that contains potential binding sites for HD and PD, but not to a -4/+36-bp fragment whose HD and PD sites have been mutated. Thus, the functional interaction of PAX3/FKHR with GLUT4-P appears to require all of the functional domains of PAX3/FKHR, as well as a -4/+36-bp region within the GLUT4 promoter. Taken together, the data suggest that the GLUT4 gene is a downstream target of PAX3/FKHR and that GLUT4 is aberrantly transactivated by this oncoprotein both in vivo and in vitro.
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PMID:PAX3/forkhead homolog in rhabdomyosarcoma oncoprotein activates glucose transporter 4 gene expression in vivo and in vitro. 1241 8


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