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.

Uncovering metabolism in rhabdomyosarcoma

“…Pax3-Foxo1 orchestrates the expression of numerous Pax3 downstream genes with increased amplitude and without feedback control, impairing the apoptosis and differentiation processes [49][50][51][52][53] and conferring a G2 checkpoint-dependent resistance to irradiation in vitro and in vivo. 54 For example, the Pax3-Foxo1-dependent transcription of genes like hepatocyte growth factor receptor (HGFR or c-MET), FGFR4, IGF-2 and C-X-C chemokine receptor type 4 (CXCR4) contributes to increase tumor aggressiveness and metastasis recurrence.…”

“…54 For example, the Pax3-Foxo1-dependent transcription of genes like hepatocyte growth factor receptor (HGFR or c-MET), FGFR4, IGF-2 and C-X-C chemokine receptor type 4 (CXCR4) contributes to increase tumor aggressiveness and metastasis recurrence. 53 In addition, the Pax3-Foxo1 fusion protein drives the oncogenic transcription of N-MYC. 37 In the metabolic context, Pax3-Foxo1 has been shown to drive transcription of GLUT4 gene, thereby eliciting increased glucose uptake in ARMS cells 55 ( Fig.…”

Cranial metastatic alveolar rhabdomyosarcoma mimicking hematological malignancy in an adolescent boy

“…A characteristic of the ARMS subtype is the occurrence of PAX3-FOXO1 as the most common fusion gene in ARMS. This fusion transcription factor is thought to drive the gene expression that causes the worse prognosis in ARMS [3,15,16]. We could not study a chromosomal analysis at the onset.…”

“…ARMS is associated with a poorer prognosis [16]. Most cases have been associated with advanced RMS presenting with bone marrow (BM) metastases.…”

“…These cases present a diagnostic problem to anyone unfamiliar with its clinical features [4, 9-11, 18, 25]. Especially, alveolar RMS with t(2;13) (q35;q14) may present with widespread disease, no discernible primary lesion, and, in some cases, may be confined to the marrow [3,15,16].…”