Key processes of apoptosis, cell proliferation, cellular
differentiation, and epigenetic homeostasis are deregulated by mutation or gene
copy-number and/or gene expression alterations in fusion negative (FN) or fusion
positive (FP) rhabdomyosarcoma (RMS). In FP RMS, chromosomal translocations
result in PAX3–FOXO1 or
PAX7–FOXO1 fusion genes. The aberrant
PAX3–FOXO1 fusion protein can synergize with loss of p16 or p53
functionality that is associated with CDKN2A gene loss and/or
promoter methylation and TP53 mutation. The stability and
subcellular localization of the PAX3–FOXO1 protein is dependent on
phosphorylation of specific sites and it works in a complex that can include
BRD4. The PAX3-FOXO1 containing complex acts as pioneer factor and drives
expression of other transcription factors such as MYCN and MYOD1 via
super-enhancers that lead to reprogramming of the transcriptional and epigenetic
landscape of tumors. The genes encoding MYCN and MYOD1 transcription factors may
themselves be genetically amplified or mutated, likely contributing to RMS
formation or progression in a subset of cases, respectively. The fusion protein
also drives expression of specific receptor tyrosine kinases (RTKs).
Overexpression and activating mutations of genes encoding the same RTKs, and
mutation of genes encoding downstream signaling components, are seen in FN RMS.
Together this leads to frequent activation of PI3K and RAS pathway signaling in
FP and FN RMS, which likely contribute to disease pathogenesis by altering cell
proliferation, apoptosis, and other metabolic pathways in ways that are not yet
precisely defined. Next-generation DNA sequencing and other molecular genetics
tools have demonstrated deleterious mutations in genes encoding certain proteins
involved in RMS pathogenesis (*). Exactly how these pathways driven RMS
pathogenesis is not clear.