Genomic and Epigenetic Changes Drive Aberrant Skeletal Muscle Differentiation in Rhabdomyosarcoma

Abstract

Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children and adolescents, represents an aberrant form of skeletal muscle differentiation. Both skeletal muscle development, as well as regeneration of adult skeletal muscle are governed by members of the myogenic family of regulatory transcription factors (MRFs), which are deployed in a highly controlled, multi-step, bidirectional process. Many aspects of this complex process are deregulated in RMS and contribute to tumorigenesis. Interconnected loops of super-enhancers, called core regulatory circuitries (CRCs), define aberrant muscle differentiation in RMS cells. The transcriptional regulation of MRF expression/activity takes a central role in the CRCs active in skeletal muscle and RMS. In PAX3::FOXO1 fusion-positive (PF+) RMS, CRCs maintain expression of the disease-driving fusion oncogene. Recent single-cell studies have revealed hierarchically organized subsets of cells within the RMS cell pool, which recapitulate developmental myogenesis and appear to drive malignancy. There is a large interest in exploiting the causes of aberrant muscle development in RMS to allow for terminal differentiation as a therapeutic strategy, for example, by interrupting MEK/ERK signaling or by interfering with the epigenetic machinery controlling CRCs. In this review, we provide an overview of the genetic and epigenetic framework of abnormal muscle differentiation in RMS, as it provides insights into fundamental mechanisms of RMS malignancy, its remarkable phenotypic diversity and, ultimately, opportunities for therapeutic intervention.

A Rare Case of Rhabdosarcoma on the Upper Pole of the Kidney

“…Rhabdomyosarcomas (RMSs) are malignant soft-tissue tumors characterized by skeletal muscle differentiation. They typically arise from chromosomal translocations involving the PAX3 gene on chromosome 2 and the FOXO1 gene on chromosome 13, leading to aberrant gene products that promote tumor formation [ 1 ]. The overall incidence of RMS in individuals below 20 years of age is 4.58 per million per year in the United States [ 2 ], with slight variations across different regions.…”

SALIQ in Rhabdomyosarcoma: A Repurposed Multidrug Regimen to Augment Standard Treatments by Adding Simvastatin, All Trans Retinoic Acid, Lithium, Itraconazole, and Quercetin

“…Children presenting with metastatic rhabdomyosarcoma have a 3-year event-free survival of 30% and overall survival of 49% after standard current cytotoxic treatments [6]. Regimens from intensive chemotherapy up to high doses with stem-cell support and radiotherapy have been tested over the years to little avail [6][7][8]. Studies like these in widely metastatic rhabdomyosarcoma using intensive chemotherapy imposed significant side effect burdens.…”

“…Rhabdomyosarcomas are histologically similar, immunohistochemical stain positive for desmin, myogenin, and MyoD but are otherwise biologically diverse [1,3,4,6]. All forms of rhabdomyosarcoma are diseases of impaired myogenic differentiation [7,8].…”