@article{5f06e873e62f4996a18935666f2d4126,
title = "Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity",
abstract = "PTEN promoter hypermethylation is nearly universal and PTEN copy number loss occurs in ~25% of fusion-negative rhabdomyosarcoma (FN-RMS). Here we show Pten deletion in a mouse model of FN-RMS results in less differentiated tumors more closely resembling human embryonal RMS. PTEN loss activated the PI3K pathway but did not increase mTOR activity. In wild-type tumors, PTEN was expressed in the nucleus suggesting loss of nuclear PTEN functions could account for these phenotypes. Pten deleted tumors had increased expression of transcription factors important in neural and skeletal muscle development including Dbx1 and Pax7. Pax7 deletion completely rescued the effects of Pten loss. Strikingly, these Pten;Pax7 deleted tumors were no longer FN-RMS but displayed smooth muscle differentiation similar to leiomyosarcoma. These data highlight how Pten loss in FN-RMS is connected to a PAX7 lineage-specific transcriptional output that creates a dependency or synthetic essentiality on the transcription factor PAX7 to maintain tumor identity.",
author = "Langdon, {Casey G.} and Gadek, {Katherine E.} and Garcia, {Matthew R.} and Evans, {Myron K.} and Reed, {Kristin B.} and Madeline Bush and Hanna, {Jason A.} and Drummond, {Catherine J.} and Maguire, {Matthew C.} and Leavey, {Patrick J.} and David Finkelstein and Hongjian Jin and Schreiner, {Patrick A.} and Rehg, {Jerold E.} and Hatley, {Mark E.}",
note = "Funding Information: We thank the SJCRH Shared Resources including Flow Cytometry and Cell Sorting (Richard Ashmun), Veterinary Pathology Core (Peter Vogel, Pam Johnson), Cell and Tissue Imaging Electron Microscopy Services (Cam Robinson), the Core Cytogenetic Laboratory (Marc Valentine, Virginia Valentine), the Hartwell Center and Functional Genomics (Geoff Neale, Melanie Loyd), and the Center for Applied Bioinformatics (Gang Wu). We thank Johnathan Dallman, Jonathan Go, D. Wood Kimbrough, and Lauren Goudie for technical assistance. Research reported in this publication supported by the National Cancer Institute of the National Institutes of Health under Award Numbers R01CA216344 and R01CA251436 (MEH) and F31CA250398 (MB). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Hatley laboratory is also supported by grants from The V Foundation for Cancer Research, the Rally Foundation for Childhood Cancer Research and Open Hands Overflowing Hearts award number 20IC23 (MEH), St. Jude Cancer Center Support Grant (P30 CA21765), and American Lebanese Syrian Associated Charities of St. Jude Children{\textquoteright}s Research Hospital. K.E.G. is supported by a Damon Runyon-Sohn Pediatric Cancer Fellowship (DRSG-30-19). Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
day = "1",
doi = "10.1038/s41467-021-25829-4",
language = "English (US)",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}