Cancer Letters

Cancer Letters

Volume 270, Issue 1, 18 October 2008, Pages 10-18
Cancer Letters

Mini-review
PAX3–FOXO1 fusion gene in rhabdomyosarcoma

https://doi.org/10.1016/j.canlet.2008.03.035Get rights and content

Abstract

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence. The predominant histologic variants of this disease are termed embryonal (eRMS) and alveolar (aRMS), based on their appearance under light microscopy. Of the two, aRMS is associated with an more aggressive disease pattern and a higher mortality, mandating a better understanding of this cancer at the molecular level. The PAX3–FOXO1 fusion gene, resulting from the stable reciprocal translocation of chromosomes 2 and 13, is a signature genetic change found only in aRMS, and thought to be responsible at least in part for its malignant phenotype. This review will discuss the clinical significance of the PAX3–FOXO1 fusion gene, the pertinent historical and current models used to study its oncogenic contributions, the transcriptional targets that are thought to mediate these contributions, and the cellular mechanisms impacted by PAX3–FOXO1 that ultimately lead to aRMS.

Introduction

Nonrandom stable reciprocal chromosomal translocations represent some of the most enigmatic mutational events found in human cancer cells. In these chromosomal translocations, previously unrelated genomic sequences are rearranged so that they are apposed, in some cases fusing the 5′ coding portion of one gene with the 3′ coding portion of another. Many of these translocation events are in-frame, generating de novo fusion genes that produce functional transcripts and, after translation, functional fusion proteins. Because these chromosomal translocations and their resulting fusion genes are found reproducibly in specific cancers, it is thought that each fusion gene is not only characteristic of a specific cancer, but also part of its genesis.

The PAX3–FOXO1 fusion gene is a signature genetic change of the pediatric cancer alveolar rhabdomyosarcoma (aRMS). PAX3-FOXO1 results from the stable reciprocal translocation of chromosomes 2 and 13, which fuses in-frame the DNA binding domain of PAX3 with the transactivation domain of FOXO1. Since both PAX3 and FOXO1 are transcription factors, this fusion results in the generation of a novel transcription factor with altered transcriptional power, potentially altered transcriptional targets, and certainly altered post-translational regulation. Although not the focus of discussion here, it should be noted that a small proportion of aRMS tumors alternatively express the PAX7-FOXO1 fusion gene, which results from a stable translocation between chromosomes 1 and 13. As prior reviews have focused on the details of the translocation locus [1], [2], and the aberrant subcellular localization that occurs in response to altered phosphorylation on the FOXO1 moiety of the PAX3–FOXO1 fusion protein [3], [4], this review will focus on the recent investigations delving into the functional contributions of PAX3–FOXO1 to aRMS tumorigenesis.

Section snippets

Clinical significance

PAX3–FOXO1 (formerly known as PAX3–FKHR) was cloned in 1993, after identification and further characterization of the t(2;13)(q35;q14) translocation, and also proven to generate the predicted fusion protein [5], [6]. As with other fusion genes, PAX3–FOXO1 was found to be specific to aRMS, and not found in any other cancer. It was not immediately clear whether the fusion gene was a bystander of the tumorigenic process of aRMS, or whether it played a role in its development. As molecular biology

Model systems to study PAX3–FOXO1

Following its cloning, the earliest studies of the oncogenic potential of PAX3–FOXO1 were performed in avian embryonic and murine embryo fibroblasts, which showed that expression of PAX3–FOXO1 could cause transformation as assessed by anchorage-independent growth in soft agar [12], [13]. However, when expressed as a single genetic change, it could not cause tumorigenesis in vivo, a finding that has been validated in subsequent studies, suggesting that although it may contribute to oncogenesis,

Transcriptional targets of PAX3–FOXO1

Regardless of the modeling strategy used to study the role of PAX3–FOXO1 in the development of aRMS, it is generally agreed that PAX3–FOXO1 exerts its tumorigenic effect at least in part through altered transcription of target genes. Early studies of its transcriptional ability, as assessed by reporter assays, showed that the fusion of the FOXO1 transactivation domain to PAX3 increased its transcriptional power [3], possibly through constitutive nuclear localization [4], loss of a cis-acting

Contribution towards tumorigenesis

Through modulation of its targets, the PAX3–FOXO1 fusion gene appears to modify key transcriptional programs in a susceptible cell, and turn on cellular pathways that endow the cell with characteristics that can contribute to the oncogenic process. While the original studies in avian and murine embryo fibroblasts showed that PAX3–FOXO1 could be transforming, they did not shed light on mechanism. As originally proposed [34], in order to form cancer, human cells need to acquire discrete

Conclusions

The PAX3–FOXO1 fusion gene results from the stable reciprocal translocation of chromosomes 2 and 13, and is found only in the cancer alveolar rhabdomyosarcoma. Expression of this fusion gene, especially in the metastatic setting, portends a very poor outcome for patients with this disease. A variety of model systems have been used to dissect the oncogenic mechanisms of PAX3–FOXO1, with the common conclusion that, alone, it is not capable of causing transformation, but must cooperate with other

Acknowledgements

This work was supported in part by grants from the NIH (5K12-HD043494), the National Childhood Cancer Research Foundation (CureSearch Scott Carter Fellowship), and Alex’s Lemonade Stand Pediatric Cancer Research Foundation. I thank Fred Barr (University of Pennsylvania) and Christopher Counter (Duke University) for helpful discussions about the PAX3–FOXO1 fusion gene, and David Parham (University of Oklahoma) for suggestions with references.

References (59)

  • J.A. Burger et al.

    CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment

    Blood

    (2006)
  • J. Libura et al.

    CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion

    Blood

    (2002)
  • O. Tomescu et al.

    Inducible short-term and stable long-term cell culture systems reveal that the PAX3–FKHR fusion oncoprotein regulates CXCR4, PAX3, and PAX7 expression

    Lab Invest.

    (2004)
  • F.G. Barr

    Fusions involving paired box and fork head family transcription factors in the pediatric cancer alveolar rhabdomyosarcoma

    Curr. Top. Microbiol. Immunol.

    (1997)
  • F.G. Barr

    The role of chimeric paired box transcription factors in the pathogenesis of pediatric rhabdomysarcoma

    Cancer Res.

    (1999)
  • W.J. Fredericks et al.

    The PAX3–FKHR fusion protein created by the t(2;13) translocation in alveolar rhabdomyosarcomas is a more potent transcriptional activator than PAX3

    Mol. Cell. Biol.

    (1995)
  • L. Del Peso et al.

    Regulation of the forkhead transcription factor FKHR, but not the PAX3–FKHR fusion protein, by the serine/threonine kinase Akt

    Oncogene

    (1999)
  • D.N. Shapiro et al.

    Fusion of PAX3 to a member of the forkhead family of transcription factors in human alveolar rhabdomyosarcoma

    Cancer Res.

    (1993)
  • N. Galili et al.

    Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma

    Nat. Genet.

    (1993)
  • A. Pinto et al.

    Undifferentiated rhabdomyosarcoma with lymphoid phenotype expression

    Med. Pediatr. Oncol.

    (1997)
  • K.M. Kelly et al.

    Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma

    J. Clin. Oncol.

    (1997)
  • J. Anderson et al.

    Detection of the PAX3–FKHR fusion gene in paediatric rhabdomyosarcoma: a reproducible predictor of outcome?

    Br. J. Cancer

    (2001)
  • P.H. Sorensen et al.

    PAX3–FKHR and PAX7–FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children’s oncology group

    J. Clin. Oncol.

    (2002)
  • S. Scheidler et al.

    The hybrid PAX3–FKHR fusion protein of alveolar rhabdomyosarcoma transforms fibroblasts in culture

    Proc. Natl. Acad. Sci. USA

    (1996)
  • P.Y. Lam et al.

    The oncogenic potential of the Pax3–FKHR fusion protein requires the Pax3 homeodomain recognition helix but not the Pax3 paired-box DNA binding domain

    Mol. Cell. Biol.

    (1999)
  • W.J. Fredericks et al.

    An engineered PAX3–KRAB transcriptional repressor inhibits the malignant phenotype of alveolar rhabdomyosarcoma cells harboring the endogenous PAX3–FKHR oncogene

    Mol. Cell. Biol.

    (2000)
  • M. Bernasconi et al.

    Induction of apoptosis in rhabdomyosarcoma cells through down-regulation of PAX proteins

    Proc. Natl. Acad. Sci. USA

    (1996)
  • M.J. Anderson et al.

    Embryonic expression of the tumor-associated PAX3–FKHR fusion protein interferes with the developmental functions of Pax3

    Proc. Natl. Acad. Sci. USA

    (2001)
  • I. Lagutina et al.

    Pax3-FKHR knock-in mice show developmental aberrations but do not develop tumors

    Mol. Cell. Biol.

    (2002)
  • Cited by (0)

    View full text