Abstract
Rhabdomyosarcoma (RMS) is a family of soft tissue cancers that are related to the skeletal muscle lineage and predominantly occur in children and young adults. A specific chromosomal translocation t(2;13)(q35;q14) that gives rise to the chimeric oncogenic transcription factor PAX3-FOXO1 has been identified as a hallmark of the aggressive alveolar subtype of RMS. PAX3-FOXO1 cooperates with additional molecular changes to promote oncogenic transformation and tumorigenesis in various human and murine models. Its expression is generally restricted to RMS tumor cells, thus providing a very specific target for therapeutic approaches for these RMS tumors. In this article, we review the recent understanding of PAX3-FOXO1 as a transcription factor in the pathogenesis of this cancer and discuss recent developments to target this oncoprotein for treatment of RMS.
Highlights
Rhabdomyosarcoma (RMS) is a heterogeneous group of malignant soft tissue tumors that share biological features with skeletal myogenesis
Gene fusions emerge as an attractive category of cancer genes, because the chimeric molecules encoded by these gene fusions are often dominant-acting drivers of tumorigenesis and usually expressed only in tumor cells
Successful therapies have been developed to directly target several fusion proteins involved in signal transduction, such as BCR-ABL in leukemia and EML4-ALK1 in lung carcinoma
Summary
Rhabdomyosarcoma (RMS) is a heterogeneous group of malignant soft tissue tumors that share biological features with skeletal myogenesis. The formation of an invariant PAX3-FOXO1 fusion in the majority of ARMS tumors further enhances its value as an attractive target for cancer treatment. PAX3-FOXO1 fusion has been found to be temporarily expressed at the mRNA and protein level during some early stages of normal myogenesis, perhaps as a result of trans-splicing of the PAX3 and FOXO1 transcripts [72,73] It appears that PAX3-FOXO1 is only capable of interfering with normal myogenesis and promoting oncogenic transformation when constantly expressed as a result of a genetic rearrangement [72]. This aberrant fusion has not been detected in normal myogenic cells in children and adults, who would be the patients treated with such targeted therapy.
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