Chromosomal Translocation t(1;13)(p36;q14) in a Case of Rhabdomyosarcoma

Biegel, Jaclyn A.; Meek, Rita; Parmiter, Annette H.; Conard, Katrina; Emanuel, Beverly S.

doi:10.1002/gcc.2870030612

Cited by 76 publications

(32 citation statements)

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“…The most prevalent ®nding in ARMS is a translocation, t(2;13)(q35-37;q14), which was detected in 70% of ARMS cases (Douglass et al, 1987;Turc-Carel et al, 1986;Wang-Wuu et al, 1988) (Figure 1). In addition, a variant translocation, t(1;13)(p36;q14), was identi®ed in a smaller subset of ARMS cases (Biegel et al, 1991;Oncogene (2001) 20, 5736 ± 5746 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc *Correspondence: FG Barr; E-mail: barrfg@mail.med.upenn.edu Douglass et al, 1991). The 2;13 and 1;13 translocations have not been detected in any other tumor type and appear to be speci®c and sensitive markers of ARMS.…”

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Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

2001

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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 e ects 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 ampli®cation 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 AKTdependent 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, di erentiation and motility. Oncogene (2001) 20, 5736 ± 5746.

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Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

2001

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“…Alveolar rhabdomyosarcoma (ARMS) is a pediatric soft tissue tumor that is associated with either a t(2;13)(q35;q14) or variant t(1;13)(p36;q14) translocation (2,3). These translocations fuse either PAX3 or PAX7 with FKHR to generate chimeric genes that express PAX3-FKHR or PAX7-FKHR fusion products, respectively (4-7).…”

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Fusion genes resulting from alternative chromosomal translocations are overexpressed by gene-specific mechanisms in alveolar rhabdomyosarcoma

Davis

Barr

1997

Proc. Natl. Acad. Sci. U.S.A.

126

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Chromosomal translocations identified in hematopoietic and solid tumors result in deregulated expression of protooncogenes or creation of chimeric proteins with tumorigenic potential. In the pediatric solid tumor alveolar rhabdomyosarcoma, a consistent t(2;13)(q35;q14) or variant t(1;13)(p36;q14) translocation generates PAX3-FKHR or PAX7-FKHR fusion proteins, respectively. In this report, we demonstrate that in addition to functional alterations these translocations are associated with fusion product overexpression. Furthermore, PAX3-FKHR and PAX7-FKHR overexpression occurs by distinct mechanisms. Transcription of PAX3-FKHR is increased relative to wild-type PAX3 by a copy number-independent process. In contrast, PAX7-FKHR overexpression results from fusion gene amplification. Thus, gene-specific mechanisms were selected to overexpress PAX3-FKHR and PAX7-FKHR in alveolar rhabdomyosarcoma, presumably due to differences in regulation between the wild-type loci. We postulate that these overexpression mechanisms ensure a critical level of gene product for the oncogenic effects of these fusions.Cytogenetics has demonstrated the presence of consistent chromosomal translocations in hematopoietic and solid malignancies (1). Molecular analysis of the consequences of these events has revealed two models for oncogene activation (1). Either protooncogene expression is deregulated by juxtaposition with strong regulatory elements or novel fusion proteins are created with altered function and tumorigenic potential.Alveolar rhabdomyosarcoma (ARMS) is a pediatric soft tissue tumor that is associated with either a t(2;13)(q35;q14) or variant t(1;13)(p36;q14) translocation (2, 3). These translocations fuse either PAX3 or PAX7 with FKHR to generate chimeric genes that express PAX3-FKHR or PAX7-FKHR fusion products, respectively (4-7). These fusion proteins consist of the N-terminal DNA-binding domains of PAX3 or PAX7 fused to the C-terminal transcriptional activation domain of FKHR. Transient transfection experiments indicate that PAX3-FKHR functions as a transcription factor (8, 9). Moreover, PAX3-FKHR exhibits increased transcriptional potency relative to PAX3 due to swapping of PAX3 and FKHR C-terminal transactivation domains. Cell culture experiments also have demonstrated that PAX3-FKHR can induce phenotypic changes, including cellular transformation (10) and inhibition of myogenic differentiation (11).While these studies of the ARMS translocations are consistent with the fusion protein model of oncogene activation, additional evidence indicates that altered expression of PAX3-FKHR and PAX7-FKHR is another fundamental characteristic of ARMS. Previous Northern blot analysis of a few ARMS cell lines demonstrated that while PAX3-FKHR RNA was readily detectable, PAX3 RNA was expressed at low or undetectable levels (4). Furthermore, amplification of the PAX3-FKHR and PAX7-FKHR fusion genes has been detected in tumor specimens (12). Finally, antisense oligonucleotide treatment of ARMS cells has shown that transient down-regu...

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“…The variant translocation t(l; 13) (p36; q 14) occurs in 5% of the tumors (Biegel et al 1991 ). The forkhead-domain (FKHR) gene on chromosome 13q 14 is fused to either of the paired box genes PAX3 in 2q35 or PAX7 in I p36 (Barret al 1993, Davis et al 1994.…”

Section: Molecular and Cytogenetics Of Soft Tissue Sarcomasmentioning

confidence: 99%

Molecular and cytogenetics of soft tissue sarcomas

Nilbert

1997

Acta Orthopaedica Scandinavica

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Chromosomal Translocation t(1;13)(p36;q14) in a Case of Rhabdomyosarcoma

Cited by 76 publications

References 6 publications

Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

Fusion genes resulting from alternative chromosomal translocations are overexpressed by gene-specific mechanisms in alveolar rhabdomyosarcoma

Molecular and cytogenetics of soft tissue sarcomas

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