Alveolar rhabdomyosarcoma - The molecular drivers of PAX3/7-FOXO1-induced tumorigenesis

Abstract

Rhabdomyosarcoma is a soft tissue sarcoma arising from cells of a mesenchymal or skeletal muscle lineage. Alveolar rhabdomyosarcoma (ARMS) is more aggressive than the more common embryonal (ERMS) subtype. ARMS is more prone to metastasis and carries a poorer prognosis. In contrast to ERMS, the majority of ARMS tumors carry one of several characteristic chromosomal translocations, such as t(2;13)(q35;q14), which results in the expression of a PAX3-FOXO1 fusion transcription factor. In this review we discuss the genes that cooperate with PAX3-FOXO1, as well as the target genes of the fusion transcription factor that contribute to various aspects of ARMS tumorigenesis. The characterization of these pathways will lead to a better understanding of ARMS tumorigenesis and will allow the design of novel targeted therapies that will lead to better treatment for this aggressive pediatric tumor.

Figure 1

Gene translocation in alveolar rhabdomyosarcoma. Scale diagram showing the parent proteins and the resulting fusion proteins arising from chromosomal translocations occurring in ARMS. Green or yellow indicates the protein fusion sites [14,19-22]. Homologous domains are indicated in like colors. DNA-binding domains are indicated as: paired domain (PD), homeodomain (HD), fork head DNA-binding domain (FH) and basic helix-loop-helix domain (bHLH). Regions of the proteins known to act as transcriptional activation domains are indicated (TAD). Other domains include the octapeptide domain (O), PAS domains (PAS A/B), LXXLL motifs (L1-L7) and glutamine-rich region (Q-rich). Maps were derived from the following references: [14,19-22,32-34].

Figure 2

Review summary: Fusion gene regulated genes contributing to alveolar rhabdomyosarcoma. Rhabdomyosarcoma develops from an unknown cell of origin from the mesodermal lineage that may be skeletal muscle specified. This cell likely expresses both PAX3/7 and FOXO1 and may also express Myf6. A gene fusion event resulting in a PAX3/7 DNA-binding domain fused to a more potent transcriptional activation domain occurs. This fusion transcription factor is capable of inducing a group of PAX3-FOXO1-regulated genes that contribute to ARMS development in conjunction with other genetic lesions.