RESUMEN
Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.
Asunto(s)
Rabdomiosarcoma Alveolar , Rabdomiosarcoma , Animales , Niño , Humanos , Ratones , Línea Celular Tumoral , Células Endoteliales/metabolismo , Proteína Forkhead Box O1/metabolismo , Regulación Neoplásica de la Expresión Génica , Músculo Esquelético/metabolismo , Proteínas de Fusión Oncogénica/genética , Factores de Transcripción Paired Box/genética , Factor de Transcripción PAX3/genética , Factor de Transcripción PAX3/metabolismo , Rabdomiosarcoma/genética , Rabdomiosarcoma/patología , Rabdomiosarcoma Alveolar/genéticaRESUMEN
BACKGROUND: Supratentorial hemangioblastomas are benign and highly vascularized neoplasms that appear most often in the spine and posterior cranial fossa. They can also be located in the supratentorial compartment of the brain. We conducted a systematic review of the literature to better understand the clinical insights of supratentorial hemangioblastoma in adults. METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the authors reviewed the English-language literature in the PubMed/MEDLINE database on supratentorial hemangioblastoma in adults, published in the past 40 years. We analyzed the differences between sporadic hemangioblastomas and hemangioblastomas associated with von Hippel-Lindau disease. In addition, we compared the characteristics of supratentorial hemangioblastomas with infratentorial and spinal cord locations. RESULTS: We reviewed 92 articles, describing 157 supratentorial hemangioblastomas in a total cohort of 148 adult patients. Most articles reporting supratentorial hemangioblastomas were published in the United States. Supratentorial hemangioblastomas occur more frequently in women than men. The median age at the time of diagnosis was 44.48 years. The sellar/parasellar region was the most commonly tumor location, while the most common morphological type was the solid type. Almost 80% of hemangioblastomas were completely resected; the outcome was favorable in more than 3 fourth of patients. CONCLUSIONS: Given their rarity, the literature on supratentorial hemangioblastomas is limited and based mostly on case reports. Complete surgical resection is the first choice of treatment and is associated with a good treatment outcome.