Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

Abstract

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.

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

“…Small round cell sarcoma is a heterogeneous group of tumors arising from various sites, and the prognosis of this disease is poor 7, 8. Fusion genes resulting from chromosomal rearrangements have been considered as a significant oncogenic factor in many mesenchymal malignancies,9 and tumor‐specific fusion genes contribute to the classification of small round cell sarcomas into several histologic subtypes,8 that is, EWSR1 – FLI1 fusion in Ewing sarcoma10 and PAX3/8 fusions in alveolar rhabdomyosarcoma 11…”

The reduced and altered activities of PAX5 are linked to the protein–protein interaction motif (coiled-coil domain) of the PAX5–PML fusion protein in t(9;15)-associated acute lymphocytic leukemia

“…The PAX3-FKHR and PAX7-FKHR fusion genes were identified in alveolar rhabdomyosarcoma patients, which are most frequent in adolescent and young adult rhabdomyosarcoma patients (Barr, 2001). The PAX8-PPARgamma chimeric gene is a molecular event associated with follicular thyroid tumorigenesis and is generated by a chromosomal rearrangement between PAX8 and PPARgamma genes (Robson et al, 2006).…”

PAX-FKHR function as pangenes by simultaneously inducing and inhibiting myogenesis

“…RMS are subdivided into two main histopathologic classes, alveolar (ARMS) and embryonal (ERMS), which differ in their clinical presentation, response to therapy and prognosis. ARMS are characterized by specific reciprocal translocations that fuse the PAX3 or PAX7 genes to FKHR (Barr, 2001). The consequence of these translocations is the expression of the PAX3-FKHR and PAX7-FKHR (collectively, PAX-FKHR) chimeric transcription factors containing the PAX DNA-binding domains and the potent FKHR transactivation domain.…”