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Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity
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 P...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448747/ https://www.ncbi.nlm.nih.gov/pubmed/34535684 http://dx.doi.org/10.1038/s41467-021-25829-4 |
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author | Langdon, Casey G. Gadek, Katherine E. Garcia, Matthew R. Evans, Myron K. Reed, Kristin B. Bush, Madeline Hanna, Jason A. Drummond, Catherine J. Maguire, Matthew C. Leavey, Patrick J. Finkelstein, David Jin, Hongjian Schreiner, Patrick A. Rehg, Jerold E. Hatley, Mark E. |
author_facet | Langdon, Casey G. Gadek, Katherine E. Garcia, Matthew R. Evans, Myron K. Reed, Kristin B. Bush, Madeline Hanna, Jason A. Drummond, Catherine J. Maguire, Matthew C. Leavey, Patrick J. Finkelstein, David Jin, Hongjian Schreiner, Patrick A. Rehg, Jerold E. Hatley, Mark E. |
author_sort | Langdon, Casey G. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8448747 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-84487472021-10-04 Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity Langdon, Casey G. Gadek, Katherine E. Garcia, Matthew R. Evans, Myron K. Reed, Kristin B. Bush, Madeline Hanna, Jason A. Drummond, Catherine J. Maguire, Matthew C. Leavey, Patrick J. Finkelstein, David Jin, Hongjian Schreiner, Patrick A. Rehg, Jerold E. Hatley, Mark E. Nat Commun Article 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. Nature Publishing Group UK 2021-09-17 /pmc/articles/PMC8448747/ /pubmed/34535684 http://dx.doi.org/10.1038/s41467-021-25829-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Langdon, Casey G. Gadek, Katherine E. Garcia, Matthew R. Evans, Myron K. Reed, Kristin B. Bush, Madeline Hanna, Jason A. Drummond, Catherine J. Maguire, Matthew C. Leavey, Patrick J. Finkelstein, David Jin, Hongjian Schreiner, Patrick A. Rehg, Jerold E. Hatley, Mark E. Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity |
title | Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity |
title_full | Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity |
title_fullStr | Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity |
title_full_unstemmed | Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity |
title_short | Synthetic essentiality between PTEN and core dependency factor PAX7 dictates rhabdomyosarcoma identity |
title_sort | synthetic essentiality between pten and core dependency factor pax7 dictates rhabdomyosarcoma identity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448747/ https://www.ncbi.nlm.nih.gov/pubmed/34535684 http://dx.doi.org/10.1038/s41467-021-25829-4 |
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