title: Acquisition of an oncogenic fusion protein serves as an initial driving mutation by inducing aneuploidy and overriding proliferative defects.
abstract: While many solid tumors are defined by the presence of a particular oncogene, the role that this oncogene plays in driving transformation through the acquisition of aneuploidy and overcoming growth arrest are often not known. Further, although aneuploidy is present in many solid tumors, it is not clear whether it is the cause or effect of malignant transformation. The childhood sarcoma, Alveolar Rhabdomyosarcoma (ARMS), is primarily defined by the t(2;13)(q35;q14) translocation, creating the PAX3-FOXO1 fusion protein. It is unclear what role PAX3-FOXO1 plays in the initial stages of tumor development through the acquisition and persistence of aneuploidy. In this study we demonstrate that PAX3-FOXO1 serves as a driver mutation to initiate a cascade of mRNA and miRNA changes that ultimately reprogram proliferating myoblasts to induce the formation of ARMS. We present evidence that cells containing PAX3-FOXO1 have changes in the expression of mRNA and miRNA essential for maintaining proper chromosome number and structure thereby promoting aneuploidy. Further, we demonstrate that the presence of PAX3-FOXO1 alters the expression of growth factor related mRNA and miRNA, thereby overriding aneuploid-dependent growth arrest. Finally, we present evidence that phosphorylation of PAX3-FOXO1 contributes to these changes. This is one of the first studies describing how an oncogene and post-translational modifications drive the development of a tumor through the acquisition and persistence of aneuploidy. This mechanism has implications for other solid tumors where large-scale genomics studies may elucidate how global alterations contribute to tumor phenotypes allowing the development of much needed multi-faceted tumor-specific therapeutic regimens.
authors: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.|Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Center, Boston, MA, USA.
authors: Jacob M
authors: JM
authors: Loupe
authors: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.|Tulane University, New Orleans, LA, USA.
authors: Patrick J
authors: PJ
authors: Miller
authors: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors: Benjamin P
authors: BP
authors: Bonner
authors: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors: Elaine C
authors: EC
authors: Maggi
authors: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors: Jyothi
authors: J
authors: Vijayaraghavan
authors: Department of Pediatrics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors: Jovanny
authors: J
authors: Zabaleta
authors: Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors: Christopher M
authors: CM
authors: Taylor
authors: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors: Fern
authors: F
authors: Tsien
authors: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors: Judy S
authors: JS
authors: Crabtree
authors: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
authors: Andrew D
authors: AD
authors: Hollenbach
mesh_terms: D000782:Aneuploidy; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002869:Chromosome Aberrations; D018450:Disease Progression; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism; D008938:Mitosis; D024510:Muscle Development; D009154:Mutation; D032446:Myoblasts / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D000072041:PAX3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D012333:RNA, Messenger
keywords: Pax3-FOXO1; alveolar rhabdomyosarcoma; aneuploidy; myogenesis; phosphorylation