Pomella Silvia, Danielli Sara G, Alaggio Rita, Breunis Willemijn B, Hamed Ebrahem, Selfe Joanna, Wachtel Marco, Walters Zoe S, Schäfer Beat W, Rota Rossella, Shipley Janet M, Hettmer Simone
Department of Hematology/Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS Istituto Ospedale Pediatrico Bambino Gesu, Viale San Paolo 15, 00146 Rome, Italy.
Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Cancers (Basel). 2023 May 18;15(10):2823. doi: 10.3390/cancers15102823.
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.
横纹肌肉瘤（RMS）是儿童和青少年中最常见的软组织肉瘤，代表了骨骼肌分化的一种异常形式。骨骼肌的发育以及成体骨骼肌的再生均受肌源性调节转录因子家族（MRFs）成员的调控，这些成员以高度受控、多步骤、双向的过程发挥作用。这一复杂过程的许多方面在RMS中失调，并促成肿瘤发生。称为核心调控回路（CRCs）的超级增强子相互连接的环，定义了RMS细胞中异常的肌肉分化。MRF表达/活性的转录调控在骨骼肌和RMS中活跃的CRCs中起核心作用。在PAX3::FOXO1融合阳性（PF+）的RMS中，CRCs维持疾病驱动融合癌基因的表达。最近的单细胞研究揭示了RMS细胞群中分层组织的细胞亚群，这些亚群重现了发育性肌发生，似乎驱动了恶性肿瘤。人们对利用RMS中异常肌肉发育的原因，以实现终末分化作为一种治疗策略有着浓厚的兴趣，例如，通过中断MEK/ERK信号传导或干扰控制CRCs的表观遗传机制。在这篇综述中，我们概述了RMS中异常肌肉分化的遗传和表观遗传框架，因为它为RMS恶性肿瘤的基本机制、其显著的表型多样性以及最终的治疗干预机会提供了见解。
